US9402916B2 - Re-directed immunotherapy - Google Patents
Re-directed immunotherapy Download PDFInfo
- Publication number
- US9402916B2 US9402916B2 US14/005,452 US201214005452A US9402916B2 US 9402916 B2 US9402916 B2 US 9402916B2 US 201214005452 A US201214005452 A US 201214005452A US 9402916 B2 US9402916 B2 US 9402916B2
- Authority
- US
- United States
- Prior art keywords
- peptidase
- cells
- cell
- subfamily
- seq
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related, expires
Links
- 238000009169 immunotherapy Methods 0.000 title description 7
- 210000004027 cell Anatomy 0.000 claims abstract description 275
- 239000000427 antigen Substances 0.000 claims abstract description 188
- 102000036639 antigens Human genes 0.000 claims abstract description 187
- 108091007433 antigens Proteins 0.000 claims abstract description 187
- 210000001744 T-lymphocyte Anatomy 0.000 claims abstract description 178
- 230000008685 targeting Effects 0.000 claims abstract description 78
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 42
- 102000035195 Peptidases Human genes 0.000 claims description 479
- 108091005804 Peptidases Proteins 0.000 claims description 479
- 206010028980 Neoplasm Diseases 0.000 claims description 139
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 122
- 241000282414 Homo sapiens Species 0.000 claims description 112
- 239000004365 Protease Substances 0.000 claims description 78
- 230000027455 binding Effects 0.000 claims description 40
- 238000009739 binding Methods 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 36
- 201000011510 cancer Diseases 0.000 claims description 23
- 230000005867 T cell response Effects 0.000 claims description 21
- 230000028993 immune response Effects 0.000 claims description 18
- 108091054437 MHC class I family Proteins 0.000 claims description 14
- 108091054438 MHC class II family Proteins 0.000 claims description 14
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims description 14
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims description 14
- 239000012634 fragment Substances 0.000 claims description 14
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims description 14
- 102100034256 Mucin-1 Human genes 0.000 claims description 13
- 241000701022 Cytomegalovirus Species 0.000 claims description 12
- -1 IgE Receptor (CD23) Chemical compound 0.000 claims description 12
- 102100040113 Tumor necrosis factor receptor superfamily member 10A Human genes 0.000 claims description 12
- 102100038080 B-cell receptor CD22 Human genes 0.000 claims description 11
- 101001133056 Homo sapiens Mucin-1 Proteins 0.000 claims description 11
- 102100038358 Prostate-specific antigen Human genes 0.000 claims description 11
- 229960005395 cetuximab Drugs 0.000 claims description 11
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 claims description 11
- 101000610605 Homo sapiens Tumor necrosis factor receptor superfamily member 10A Proteins 0.000 claims description 10
- 108010072866 Prostate-Specific Antigen Proteins 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 102100026802 72 kDa type IV collagenase Human genes 0.000 claims description 9
- 101000756756 Homo sapiens Disintegrin and metalloproteinase domain-containing protein 28 Proteins 0.000 claims description 9
- 239000012528 membrane Substances 0.000 claims description 9
- 229960004641 rituximab Drugs 0.000 claims description 9
- 102100022820 Disintegrin and metalloproteinase domain-containing protein 28 Human genes 0.000 claims description 8
- 102100030216 Matrix metalloproteinase-14 Human genes 0.000 claims description 8
- 230000003612 virological effect Effects 0.000 claims description 8
- 102100039939 Growth/differentiation factor 8 Human genes 0.000 claims description 7
- 102100022623 Hepatocyte growth factor receptor Human genes 0.000 claims description 7
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 claims description 7
- 101001013150 Homo sapiens Interstitial collagenase Proteins 0.000 claims description 7
- 101000990915 Homo sapiens Stromelysin-1 Proteins 0.000 claims description 7
- 102100027998 Macrophage metalloelastase Human genes 0.000 claims description 7
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 claims description 7
- 102000005741 Metalloproteases Human genes 0.000 claims description 7
- 108010006035 Metalloproteases Proteins 0.000 claims description 7
- 102100023123 Mucin-16 Human genes 0.000 claims description 7
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 claims description 7
- 102100027347 Neural cell adhesion molecule 1 Human genes 0.000 claims description 7
- 102100030416 Stromelysin-1 Human genes 0.000 claims description 7
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 claims description 7
- 230000014509 gene expression Effects 0.000 claims description 7
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 claims description 6
- 102100025221 CD70 antigen Human genes 0.000 claims description 6
- 102100024423 Carbonic anhydrase 9 Human genes 0.000 claims description 6
- 102000004225 Cathepsin B Human genes 0.000 claims description 6
- 108090000712 Cathepsin B Proteins 0.000 claims description 6
- 102000003908 Cathepsin D Human genes 0.000 claims description 6
- 108090000258 Cathepsin D Proteins 0.000 claims description 6
- 102000004178 Cathepsin E Human genes 0.000 claims description 6
- 108090000611 Cathepsin E Proteins 0.000 claims description 6
- 102000004173 Cathepsin G Human genes 0.000 claims description 6
- 108090000617 Cathepsin G Proteins 0.000 claims description 6
- 108010066687 Epithelial Cell Adhesion Molecule Proteins 0.000 claims description 6
- 108010088842 Fibrinolysin Proteins 0.000 claims description 6
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 claims description 6
- 101000577881 Homo sapiens Macrophage metalloelastase Proteins 0.000 claims description 6
- 101000623901 Homo sapiens Mucin-16 Proteins 0.000 claims description 6
- 101000577877 Homo sapiens Stromelysin-3 Proteins 0.000 claims description 6
- 101000851370 Homo sapiens Tumor necrosis factor receptor superfamily member 9 Proteins 0.000 claims description 6
- 102000043129 MHC class I family Human genes 0.000 claims description 6
- 102100028762 Neuropilin-1 Human genes 0.000 claims description 6
- 101710120463 Prostate stem cell antigen Proteins 0.000 claims description 6
- 102100036735 Prostate stem cell antigen Human genes 0.000 claims description 6
- 102100028847 Stromelysin-3 Human genes 0.000 claims description 6
- 108090000190 Thrombin Proteins 0.000 claims description 6
- 102100036856 Tumor necrosis factor receptor superfamily member 9 Human genes 0.000 claims description 6
- 229940012957 plasmin Drugs 0.000 claims description 6
- 229960004072 thrombin Drugs 0.000 claims description 6
- LKDMKWNDBAVNQZ-UHFFFAOYSA-N 4-[[1-[[1-[2-[[1-(4-nitroanilino)-1-oxo-3-phenylpropan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)NC(C)C(=O)NC(C)C(=O)N1CCCC1C(=O)NC(C(=O)NC=1C=CC(=CC=1)[N+]([O-])=O)CC1=CC=CC=C1 LKDMKWNDBAVNQZ-UHFFFAOYSA-N 0.000 claims description 5
- 102000005572 Cathepsin A Human genes 0.000 claims description 5
- 108010059081 Cathepsin A Proteins 0.000 claims description 5
- 102000004172 Cathepsin L Human genes 0.000 claims description 5
- 108090000624 Cathepsin L Proteins 0.000 claims description 5
- 108090000613 Cathepsin S Proteins 0.000 claims description 5
- 102100035654 Cathepsin S Human genes 0.000 claims description 5
- 102100027995 Collagenase 3 Human genes 0.000 claims description 5
- 101000934356 Homo sapiens CD70 antigen Proteins 0.000 claims description 5
- 101000577887 Homo sapiens Collagenase 3 Proteins 0.000 claims description 5
- 101000972946 Homo sapiens Hepatocyte growth factor receptor Proteins 0.000 claims description 5
- 101000990912 Homo sapiens Matrilysin Proteins 0.000 claims description 5
- 101001011887 Homo sapiens Matrix metalloproteinase-17 Proteins 0.000 claims description 5
- 101000627852 Homo sapiens Matrix metalloproteinase-25 Proteins 0.000 claims description 5
- 101000627854 Homo sapiens Matrix metalloproteinase-26 Proteins 0.000 claims description 5
- 101000627861 Homo sapiens Matrix metalloproteinase-28 Proteins 0.000 claims description 5
- 101000990902 Homo sapiens Matrix metalloproteinase-9 Proteins 0.000 claims description 5
- 101000990908 Homo sapiens Neutrophil collagenase Proteins 0.000 claims description 5
- 101000577874 Homo sapiens Stromelysin-2 Proteins 0.000 claims description 5
- 102000043131 MHC class II family Human genes 0.000 claims description 5
- 102100030417 Matrilysin Human genes 0.000 claims description 5
- 102100030219 Matrix metalloproteinase-17 Human genes 0.000 claims description 5
- 102100024131 Matrix metalloproteinase-25 Human genes 0.000 claims description 5
- 102100024128 Matrix metalloproteinase-26 Human genes 0.000 claims description 5
- 102100026799 Matrix metalloproteinase-28 Human genes 0.000 claims description 5
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 claims description 5
- 108090000028 Neprilysin Proteins 0.000 claims description 5
- 102000003729 Neprilysin Human genes 0.000 claims description 5
- 102100030411 Neutrophil collagenase Human genes 0.000 claims description 5
- 241000700584 Simplexvirus Species 0.000 claims description 5
- 102100028848 Stromelysin-2 Human genes 0.000 claims description 5
- 102100035721 Syndecan-1 Human genes 0.000 claims description 5
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 claims description 5
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 claims description 4
- 108700012439 CA9 Proteins 0.000 claims description 4
- 102000005600 Cathepsins Human genes 0.000 claims description 4
- 108010084457 Cathepsins Proteins 0.000 claims description 4
- 101000627872 Homo sapiens 72 kDa type IV collagenase Proteins 0.000 claims description 4
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 claims description 4
- 101001011884 Homo sapiens Matrix metalloproteinase-15 Proteins 0.000 claims description 4
- 101001011886 Homo sapiens Matrix metalloproteinase-16 Proteins 0.000 claims description 4
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 claims description 4
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 claims description 4
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 claims description 4
- 241000701044 Human gammaherpesvirus 4 Species 0.000 claims description 4
- 102100030201 Matrix metalloproteinase-15 Human genes 0.000 claims description 4
- 102100030200 Matrix metalloproteinase-16 Human genes 0.000 claims description 4
- 102100024130 Matrix metalloproteinase-23 Human genes 0.000 claims description 4
- 102000003735 Mesothelin Human genes 0.000 claims description 4
- 108090000015 Mesothelin Proteins 0.000 claims description 4
- 108090000772 Neuropilin-1 Proteins 0.000 claims description 4
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 claims description 4
- 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 claims description 4
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 claims description 4
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 claims description 4
- 101150013553 CD40 gene Proteins 0.000 claims description 3
- 102000000905 Cadherin Human genes 0.000 claims description 3
- 108050007957 Cadherin Proteins 0.000 claims description 3
- 101150029707 ERBB2 gene Proteins 0.000 claims description 3
- 102000018651 Epithelial Cell Adhesion Molecule Human genes 0.000 claims description 3
- 102100030595 HLA class II histocompatibility antigen gamma chain Human genes 0.000 claims description 3
- 101000886562 Homo sapiens Growth/differentiation factor 8 Proteins 0.000 claims description 3
- 101001082627 Homo sapiens HLA class II histocompatibility antigen gamma chain Proteins 0.000 claims description 3
- 101001013139 Homo sapiens Matrix metalloproteinase-20 Proteins 0.000 claims description 3
- 101000972282 Homo sapiens Mucin-5AC Proteins 0.000 claims description 3
- 101000581981 Homo sapiens Neural cell adhesion molecule 1 Proteins 0.000 claims description 3
- 101000874179 Homo sapiens Syndecan-1 Proteins 0.000 claims description 3
- 108010073816 IgE Receptors Proteins 0.000 claims description 3
- 102100022496 Mucin-5AC Human genes 0.000 claims description 3
- 108010056852 Myostatin Proteins 0.000 claims description 3
- 102000012479 Serine Proteases Human genes 0.000 claims description 3
- 108010022999 Serine Proteases Proteins 0.000 claims description 3
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 claims description 3
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 claims description 3
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 claims description 3
- JFINOWIINSTUNY-UHFFFAOYSA-N pyrrolidin-3-ylmethanesulfonamide Chemical compound NS(=O)(=O)CC1CCNC1 JFINOWIINSTUNY-UHFFFAOYSA-N 0.000 claims description 3
- 102000004580 Aspartic Acid Proteases Human genes 0.000 claims description 2
- 108010017640 Aspartic Acid Proteases Proteins 0.000 claims description 2
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 claims description 2
- 241000189662 Calla Species 0.000 claims description 2
- 102000005927 Cysteine Proteases Human genes 0.000 claims description 2
- 108010005843 Cysteine Proteases Proteins 0.000 claims description 2
- 241000709661 Enterovirus Species 0.000 claims description 2
- 108010055196 EphA2 Receptor Proteins 0.000 claims description 2
- 102100030340 Ephrin type-A receptor 2 Human genes 0.000 claims description 2
- 102000010956 Glypican Human genes 0.000 claims description 2
- 108050001154 Glypican Proteins 0.000 claims description 2
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 claims description 2
- 101001013142 Homo sapiens Matrix metalloproteinase-21 Proteins 0.000 claims description 2
- 101000627858 Homo sapiens Matrix metalloproteinase-24 Proteins 0.000 claims description 2
- 101000799194 Homo sapiens Serine/threonine-protein kinase receptor R3 Proteins 0.000 claims description 2
- 101000835745 Homo sapiens Teratocarcinoma-derived growth factor 1 Proteins 0.000 claims description 2
- 241000701085 Human alphaherpesvirus 3 Species 0.000 claims description 2
- 102000009438 IgE Receptors Human genes 0.000 claims description 2
- 102100024129 Matrix metalloproteinase-24 Human genes 0.000 claims description 2
- 101100490437 Mus musculus Acvrl1 gene Proteins 0.000 claims description 2
- 101100369076 Mus musculus Tdgf1 gene Proteins 0.000 claims description 2
- 101150038994 PDGFRA gene Proteins 0.000 claims description 2
- 102100034136 Serine/threonine-protein kinase receptor R3 Human genes 0.000 claims description 2
- 102100026404 Teratocarcinoma-derived growth factor 1 Human genes 0.000 claims description 2
- 108090000440 matrix metalloproteinase 25 Proteins 0.000 claims description 2
- 230000007030 peptide scission Effects 0.000 claims description 2
- 229960000187 tissue plasminogen activator Drugs 0.000 claims description 2
- 241000701161 unidentified adenovirus Species 0.000 claims description 2
- 229960005356 urokinase Drugs 0.000 claims description 2
- 108091022885 ADAM Proteins 0.000 claims 1
- 102000029791 ADAM Human genes 0.000 claims 1
- 108091022879 ADAMTS Proteins 0.000 claims 1
- 102000029750 ADAMTS Human genes 0.000 claims 1
- ORILYTVJVMAKLC-UHFFFAOYSA-N Adamantane Natural products C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 claims 1
- 108700028369 Alleles Proteins 0.000 claims 1
- 102100039496 Choline transporter-like protein 4 Human genes 0.000 claims 1
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 claims 1
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 claims 1
- 101001011906 Homo sapiens Matrix metalloproteinase-14 Proteins 0.000 claims 1
- 101150073847 Mmp23 gene Proteins 0.000 claims 1
- 108091007561 SLC44A4 Proteins 0.000 claims 1
- 229940124597 therapeutic agent Drugs 0.000 claims 1
- 241000712461 unidentified influenza virus Species 0.000 claims 1
- 238000003776 cleavage reaction Methods 0.000 abstract description 97
- 230000007017 scission Effects 0.000 abstract description 97
- 235000019833 protease Nutrition 0.000 description 409
- 201000009030 Carcinoma Diseases 0.000 description 98
- 206010025323 Lymphomas Diseases 0.000 description 88
- 235000018102 proteins Nutrition 0.000 description 86
- 102000004169 proteins and genes Human genes 0.000 description 86
- 108090000623 proteins and genes Proteins 0.000 description 86
- 208000032839 leukemia Diseases 0.000 description 68
- 235000019419 proteases Nutrition 0.000 description 50
- 210000003719 b-lymphocyte Anatomy 0.000 description 40
- 101800001753 Protease Proteins 0.000 description 36
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 36
- 210000000349 chromosome Anatomy 0.000 description 36
- 241001430294 unidentified retrovirus Species 0.000 description 33
- 206010039491 Sarcoma Diseases 0.000 description 32
- 102000004196 processed proteins & peptides Human genes 0.000 description 32
- 210000004881 tumor cell Anatomy 0.000 description 32
- 230000003211 malignant effect Effects 0.000 description 30
- 210000001519 tissue Anatomy 0.000 description 23
- 102000005962 receptors Human genes 0.000 description 20
- 108020003175 receptors Proteins 0.000 description 20
- 230000036210 malignancy Effects 0.000 description 19
- 208000023275 Autoimmune disease Diseases 0.000 description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 18
- 101000616435 Homo sapiens Gamma-sarcoglycan Proteins 0.000 description 17
- 206010006187 Breast cancer Diseases 0.000 description 15
- 230000001363 autoimmune Effects 0.000 description 15
- 201000010099 disease Diseases 0.000 description 15
- 229920002521 macromolecule Polymers 0.000 description 15
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 14
- 102100037942 Suppressor of tumorigenicity 14 protein Human genes 0.000 description 14
- 102000006640 gamma-Glutamyltransferase Human genes 0.000 description 14
- 210000002307 prostate Anatomy 0.000 description 14
- 102000018713 Histocompatibility Antigens Class II Human genes 0.000 description 13
- 102100040247 Tumor necrosis factor Human genes 0.000 description 13
- 210000000612 antigen-presenting cell Anatomy 0.000 description 13
- 239000002243 precursor Substances 0.000 description 13
- 208000026310 Breast neoplasm Diseases 0.000 description 12
- 108020004206 Gamma-glutamyltransferase Proteins 0.000 description 12
- 102000008949 Histocompatibility Antigens Class I Human genes 0.000 description 12
- 101000798702 Homo sapiens Transmembrane protease serine 4 Proteins 0.000 description 12
- 241000701024 Human betaherpesvirus 5 Species 0.000 description 12
- 102100032471 Transmembrane protease serine 4 Human genes 0.000 description 12
- 230000000172 allergic effect Effects 0.000 description 12
- 208000010668 atopic eczema Diseases 0.000 description 12
- 102100024940 Cathepsin K Human genes 0.000 description 11
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 11
- 210000000481 breast Anatomy 0.000 description 11
- 210000004072 lung Anatomy 0.000 description 11
- 108090000155 pancreatic elastase II Proteins 0.000 description 11
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 11
- 102100031940 Epithelial cell adhesion molecule Human genes 0.000 description 10
- 102100033174 Neutrophil elastase Human genes 0.000 description 10
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 10
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 10
- 208000026935 allergic disease Diseases 0.000 description 10
- 230000002757 inflammatory effect Effects 0.000 description 10
- 230000037361 pathway Effects 0.000 description 10
- 238000012545 processing Methods 0.000 description 10
- 230000001225 therapeutic effect Effects 0.000 description 10
- 102100021435 Macrophage-stimulating protein receptor Human genes 0.000 description 9
- 108010067372 Pancreatic elastase Proteins 0.000 description 9
- 102000016387 Pancreatic elastase Human genes 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 235000001014 amino acid Nutrition 0.000 description 9
- 229940024606 amino acid Drugs 0.000 description 9
- 150000001413 amino acids Chemical class 0.000 description 9
- 238000013459 approach Methods 0.000 description 9
- 125000005647 linker group Chemical group 0.000 description 9
- 230000007246 mechanism Effects 0.000 description 9
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 8
- 108020002908 Epoxide hydrolase Proteins 0.000 description 8
- 102000005486 Epoxide hydrolase Human genes 0.000 description 8
- 101710087165 Mesoderm-specific transcript protein Proteins 0.000 description 8
- 102100032452 Transmembrane protease serine 6 Human genes 0.000 description 8
- 210000001072 colon Anatomy 0.000 description 8
- 239000000562 conjugate Substances 0.000 description 8
- 210000002865 immune cell Anatomy 0.000 description 8
- 238000000338 in vitro Methods 0.000 description 8
- 150000002632 lipids Chemical class 0.000 description 8
- 108010047374 matriptase 2 Proteins 0.000 description 8
- 201000001441 melanoma Diseases 0.000 description 8
- 108091007505 ADAM17 Proteins 0.000 description 7
- 102100025475 Carcinoembryonic antigen-related cell adhesion molecule 5 Human genes 0.000 description 7
- 102000004127 Cytokines Human genes 0.000 description 7
- 108090000695 Cytokines Proteins 0.000 description 7
- 102000001301 EGF receptor Human genes 0.000 description 7
- 101001106413 Homo sapiens Macrophage-stimulating protein receptor Proteins 0.000 description 7
- 108010076557 Matrix Metalloproteinase 14 Proteins 0.000 description 7
- 241000699660 Mus musculus Species 0.000 description 7
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 7
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 7
- 102100026890 Tumor necrosis factor ligand superfamily member 4 Human genes 0.000 description 7
- 230000014102 antigen processing and presentation of exogenous peptide antigen via MHC class I Effects 0.000 description 7
- 230000003197 catalytic effect Effects 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 230000004927 fusion Effects 0.000 description 7
- 230000002496 gastric effect Effects 0.000 description 7
- 210000003734 kidney Anatomy 0.000 description 7
- 201000000050 myeloid neoplasm Diseases 0.000 description 7
- 230000002611 ovarian Effects 0.000 description 7
- 229920001184 polypeptide Polymers 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- 230000003248 secreting effect Effects 0.000 description 7
- 238000002560 therapeutic procedure Methods 0.000 description 7
- 125000003396 thiol group Chemical group [H]S* 0.000 description 7
- 108091007507 ADAM12 Proteins 0.000 description 6
- 208000003950 B-cell lymphoma Diseases 0.000 description 6
- 208000003174 Brain Neoplasms Diseases 0.000 description 6
- 102100037853 C-C chemokine receptor type 4 Human genes 0.000 description 6
- 102100023336 Chymotrypsin-like elastase family member 3B Human genes 0.000 description 6
- 102100031111 Disintegrin and metalloproteinase domain-containing protein 17 Human genes 0.000 description 6
- 101000777455 Homo sapiens Disintegrin and metalloproteinase domain-containing protein 15 Proteins 0.000 description 6
- 101000832769 Homo sapiens Disintegrin and metalloproteinase domain-containing protein 9 Proteins 0.000 description 6
- 101000872580 Homo sapiens Serine protease hepsin Proteins 0.000 description 6
- 101000661807 Homo sapiens Suppressor of tumorigenicity 14 protein Proteins 0.000 description 6
- 101000638154 Homo sapiens Transmembrane protease serine 2 Proteins 0.000 description 6
- 108010002350 Interleukin-2 Proteins 0.000 description 6
- 102000000588 Interleukin-2 Human genes 0.000 description 6
- 102000004388 Interleukin-4 Human genes 0.000 description 6
- 108090000978 Interleukin-4 Proteins 0.000 description 6
- 206010035226 Plasma cell myeloma Diseases 0.000 description 6
- 102100029198 SLAM family member 7 Human genes 0.000 description 6
- 102100034801 Serine protease hepsin Human genes 0.000 description 6
- 102100031989 Transmembrane protease serine 2 Human genes 0.000 description 6
- 102100024568 Tumor necrosis factor ligand superfamily member 11 Human genes 0.000 description 6
- 102000009524 Vascular Endothelial Growth Factor A Human genes 0.000 description 6
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 6
- 230000030741 antigen processing and presentation Effects 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 239000011159 matrix material Substances 0.000 description 6
- 229960005486 vaccine Drugs 0.000 description 6
- 102100030310 5,6-dihydroxyindole-2-carboxylic acid oxidase Human genes 0.000 description 5
- 108091007504 ADAM10 Proteins 0.000 description 5
- 108091005672 ADAMTS15 Proteins 0.000 description 5
- 208000024827 Alzheimer disease Diseases 0.000 description 5
- 102100023995 Beta-nerve growth factor Human genes 0.000 description 5
- 102100032937 CD40 ligand Human genes 0.000 description 5
- 108090000625 Cathepsin K Proteins 0.000 description 5
- 101710177066 Cathepsin O Proteins 0.000 description 5
- 102100031112 Disintegrin and metalloproteinase domain-containing protein 12 Human genes 0.000 description 5
- 102100031113 Disintegrin and metalloproteinase domain-containing protein 15 Human genes 0.000 description 5
- 102100024361 Disintegrin and metalloproteinase domain-containing protein 9 Human genes 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 108010069446 Fertilins Proteins 0.000 description 5
- 102000001133 Fertilins Human genes 0.000 description 5
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 5
- 102100028972 HLA class I histocompatibility antigen, A alpha chain Human genes 0.000 description 5
- 108010075704 HLA-A Antigens Proteins 0.000 description 5
- 102100034459 Hepatitis A virus cellular receptor 1 Human genes 0.000 description 5
- 101000777464 Homo sapiens Disintegrin and metalloproteinase domain-containing protein 19 Proteins 0.000 description 5
- 101000689659 Homo sapiens Disintegrin and metalloproteinase domain-containing protein 21 Proteins 0.000 description 5
- 101000832767 Homo sapiens Disintegrin and metalloproteinase domain-containing protein 8 Proteins 0.000 description 5
- 101000920667 Homo sapiens Epithelial cell adhesion molecule Proteins 0.000 description 5
- 101001100327 Homo sapiens RNA-binding protein 45 Proteins 0.000 description 5
- 101000633784 Homo sapiens SLAM family member 7 Proteins 0.000 description 5
- 101000764263 Homo sapiens Tumor necrosis factor ligand superfamily member 4 Proteins 0.000 description 5
- 101000610604 Homo sapiens Tumor necrosis factor receptor superfamily member 10B Proteins 0.000 description 5
- 108060003951 Immunoglobulin Proteins 0.000 description 5
- 102000004889 Interleukin-6 Human genes 0.000 description 5
- 108090001005 Interleukin-6 Proteins 0.000 description 5
- 108010016165 Matrix Metalloproteinase 2 Proteins 0.000 description 5
- 108010063954 Mucins Proteins 0.000 description 5
- 102000015728 Mucins Human genes 0.000 description 5
- 206010033128 Ovarian cancer Diseases 0.000 description 5
- 102100038823 RNA-binding protein 45 Human genes 0.000 description 5
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 5
- 108091008874 T cell receptors Proteins 0.000 description 5
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 5
- 102000001400 Tryptase Human genes 0.000 description 5
- 108060005989 Tryptase Proteins 0.000 description 5
- 102100036922 Tumor necrosis factor ligand superfamily member 13B Human genes 0.000 description 5
- 102100040112 Tumor necrosis factor receptor superfamily member 10B Human genes 0.000 description 5
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 5
- 239000012190 activator Substances 0.000 description 5
- 208000009956 adenocarcinoma Diseases 0.000 description 5
- 210000004204 blood vessel Anatomy 0.000 description 5
- 230000000295 complement effect Effects 0.000 description 5
- 231100000433 cytotoxic Toxicity 0.000 description 5
- 230000001472 cytotoxic effect Effects 0.000 description 5
- 230000009977 dual effect Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229940088598 enzyme Drugs 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 239000003102 growth factor Substances 0.000 description 5
- 102000018358 immunoglobulin Human genes 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 210000004698 lymphocyte Anatomy 0.000 description 5
- 210000000056 organ Anatomy 0.000 description 5
- 210000000496 pancreas Anatomy 0.000 description 5
- 208000000587 small cell lung carcinoma Diseases 0.000 description 5
- 102100033400 4F2 cell-surface antigen heavy chain Human genes 0.000 description 4
- 102100032309 A disintegrin and metalloproteinase with thrombospondin motifs 15 Human genes 0.000 description 4
- 108091005660 ADAMTS1 Proteins 0.000 description 4
- 108091005668 ADAMTS10 Proteins 0.000 description 4
- 108091005671 ADAMTS12 Proteins 0.000 description 4
- 108091005670 ADAMTS13 Proteins 0.000 description 4
- 108091005673 ADAMTS14 Proteins 0.000 description 4
- 108091005675 ADAMTS16 Proteins 0.000 description 4
- 108091005674 ADAMTS17 Proteins 0.000 description 4
- 108091005568 ADAMTS18 Proteins 0.000 description 4
- 108091005570 ADAMTS19 Proteins 0.000 description 4
- 108091005569 ADAMTS20 Proteins 0.000 description 4
- 108091005661 ADAMTS3 Proteins 0.000 description 4
- 108091005664 ADAMTS4 Proteins 0.000 description 4
- 108091005663 ADAMTS5 Proteins 0.000 description 4
- 108091005665 ADAMTS6 Proteins 0.000 description 4
- 108091005667 ADAMTS7 Proteins 0.000 description 4
- 108091005666 ADAMTS8 Proteins 0.000 description 4
- 108091005669 ADAMTS9 Proteins 0.000 description 4
- 102100031585 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Human genes 0.000 description 4
- 102100026423 Adhesion G protein-coupled receptor E5 Human genes 0.000 description 4
- 102100036791 Adhesion G protein-coupled receptor L2 Human genes 0.000 description 4
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 4
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 4
- 102100032412 Basigin Human genes 0.000 description 4
- 101100284398 Bos taurus BoLA-DQB gene Proteins 0.000 description 4
- 102000004176 Cathepsin F Human genes 0.000 description 4
- 108090000610 Cathepsin F Proteins 0.000 description 4
- 102000004175 Cathepsin H Human genes 0.000 description 4
- 108090000619 Cathepsin H Proteins 0.000 description 4
- 102100026540 Cathepsin L2 Human genes 0.000 description 4
- 102000011933 Cathepsin W Human genes 0.000 description 4
- 108010061112 Cathepsin W Proteins 0.000 description 4
- 108010012236 Chemokines Proteins 0.000 description 4
- 102000019034 Chemokines Human genes 0.000 description 4
- 101710138848 Chymotrypsin-like elastase family member 1 Proteins 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 4
- 101001077839 Corynebacterium sp. (strain C12) Soluble epoxide hydrolase Proteins 0.000 description 4
- 102000003779 Dipeptidyl-peptidases and tripeptidyl-peptidases Human genes 0.000 description 4
- 108090000194 Dipeptidyl-peptidases and tripeptidyl-peptidases Proteins 0.000 description 4
- 102100039673 Disintegrin and metalloproteinase domain-containing protein 10 Human genes 0.000 description 4
- 102100031107 Disintegrin and metalloproteinase domain-containing protein 11 Human genes 0.000 description 4
- 102100031098 Disintegrin and metalloproteinase domain-containing protein 18 Human genes 0.000 description 4
- 102100031116 Disintegrin and metalloproteinase domain-containing protein 19 Human genes 0.000 description 4
- 102100022825 Disintegrin and metalloproteinase domain-containing protein 22 Human genes 0.000 description 4
- 102100022817 Disintegrin and metalloproteinase domain-containing protein 29 Human genes 0.000 description 4
- 102100024362 Disintegrin and metalloproteinase domain-containing protein 7 Human genes 0.000 description 4
- 102100024364 Disintegrin and metalloproteinase domain-containing protein 8 Human genes 0.000 description 4
- 108060006698 EGF receptor Proteins 0.000 description 4
- 101710099240 Elastase-1 Proteins 0.000 description 4
- 102000010451 Folate receptor alpha Human genes 0.000 description 4
- 108050001931 Folate receptor alpha Proteins 0.000 description 4
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 4
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 4
- ZWQVYZXPYSYPJD-RYUDHWBXSA-N Glu-Gly-Phe Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZWQVYZXPYSYPJD-RYUDHWBXSA-N 0.000 description 4
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 description 4
- 102000003886 Glycoproteins Human genes 0.000 description 4
- 108090000288 Glycoproteins Proteins 0.000 description 4
- 102000001398 Granzyme Human genes 0.000 description 4
- 102000003745 Hepatocyte Growth Factor Human genes 0.000 description 4
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 description 4
- 108010088652 Histocompatibility Antigens Class I Proteins 0.000 description 4
- 108010027412 Histocompatibility Antigens Class II Proteins 0.000 description 4
- 101000718243 Homo sapiens Adhesion G protein-coupled receptor E5 Proteins 0.000 description 4
- 101000738584 Homo sapiens C-C chemokine receptor type 4 Proteins 0.000 description 4
- 101000897480 Homo sapiens C-C motif chemokine 2 Proteins 0.000 description 4
- 101000777452 Homo sapiens Disintegrin and metalloproteinase domain-containing protein 11 Proteins 0.000 description 4
- 101000777467 Homo sapiens Disintegrin and metalloproteinase domain-containing protein 18 Proteins 0.000 description 4
- 101000689653 Homo sapiens Disintegrin and metalloproteinase domain-containing protein 20 Proteins 0.000 description 4
- 101000756722 Homo sapiens Disintegrin and metalloproteinase domain-containing protein 22 Proteins 0.000 description 4
- 101000756746 Homo sapiens Disintegrin and metalloproteinase domain-containing protein 29 Proteins 0.000 description 4
- 101000720046 Homo sapiens Disintegrin and metalloproteinase domain-containing protein 30 Proteins 0.000 description 4
- 101000720049 Homo sapiens Disintegrin and metalloproteinase domain-containing protein 33 Proteins 0.000 description 4
- 101000832771 Homo sapiens Disintegrin and metalloproteinase domain-containing protein 7 Proteins 0.000 description 4
- 101001011896 Homo sapiens Matrix metalloproteinase-19 Proteins 0.000 description 4
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 4
- 101001129796 Homo sapiens p53-induced death domain-containing protein 1 Proteins 0.000 description 4
- 241000725303 Human immunodeficiency virus Species 0.000 description 4
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 4
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 4
- 102100037877 Intercellular adhesion molecule 1 Human genes 0.000 description 4
- 102100037871 Intercellular adhesion molecule 3 Human genes 0.000 description 4
- 102100026878 Interleukin-2 receptor subunit alpha Human genes 0.000 description 4
- 102100037792 Interleukin-6 receptor subunit alpha Human genes 0.000 description 4
- 102100038007 Low affinity immunoglobulin epsilon Fc receptor Human genes 0.000 description 4
- 102100026894 Lymphotoxin-beta Human genes 0.000 description 4
- 102100030218 Matrix metalloproteinase-19 Human genes 0.000 description 4
- 108020002334 Monoacylglycerol lipase Proteins 0.000 description 4
- 102100029814 Monoglyceride lipase Human genes 0.000 description 4
- 108700026244 Open Reading Frames Proteins 0.000 description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 description 4
- 102100023472 P-selectin Human genes 0.000 description 4
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 4
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 4
- 102100033237 Pro-epidermal growth factor Human genes 0.000 description 4
- 101710098940 Pro-epidermal growth factor Proteins 0.000 description 4
- 102100023832 Prolyl endopeptidase FAP Human genes 0.000 description 4
- 102100029831 Reticulon-4 Human genes 0.000 description 4
- 206010042971 T-cell lymphoma Diseases 0.000 description 4
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 4
- 102100025237 T-cell surface antigen CD2 Human genes 0.000 description 4
- 108090000631 Trypsin Proteins 0.000 description 4
- 102000004142 Trypsin Human genes 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 239000000611 antibody drug conjugate Substances 0.000 description 4
- 229940049595 antibody-drug conjugate Drugs 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 4
- 238000003384 imaging method Methods 0.000 description 4
- 230000002637 immunotoxin Effects 0.000 description 4
- 229940051026 immunotoxin Drugs 0.000 description 4
- 239000002596 immunotoxin Substances 0.000 description 4
- 231100000608 immunotoxin Toxicity 0.000 description 4
- 102000006495 integrins Human genes 0.000 description 4
- 108010044426 integrins Proteins 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- 230000002147 killing effect Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 210000000822 natural killer cell Anatomy 0.000 description 4
- 230000001537 neural effect Effects 0.000 description 4
- 208000015122 neurodegenerative disease Diseases 0.000 description 4
- 108020004707 nucleic acids Proteins 0.000 description 4
- 102000039446 nucleic acids Human genes 0.000 description 4
- 150000007523 nucleic acids Chemical class 0.000 description 4
- 102100031691 p53-induced death domain-containing protein 1 Human genes 0.000 description 4
- 239000000863 peptide conjugate Substances 0.000 description 4
- 210000004180 plasmocyte Anatomy 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 239000012588 trypsin Substances 0.000 description 4
- 230000002792 vascular Effects 0.000 description 4
- 102100027398 A disintegrin and metalloproteinase with thrombospondin motifs 1 Human genes 0.000 description 3
- 102100032295 A disintegrin and metalloproteinase with thrombospondin motifs 10 Human genes 0.000 description 3
- 102100032296 A disintegrin and metalloproteinase with thrombospondin motifs 12 Human genes 0.000 description 3
- 102100032290 A disintegrin and metalloproteinase with thrombospondin motifs 13 Human genes 0.000 description 3
- 102100032310 A disintegrin and metalloproteinase with thrombospondin motifs 14 Human genes 0.000 description 3
- 102100032291 A disintegrin and metalloproteinase with thrombospondin motifs 16 Human genes 0.000 description 3
- 102100032292 A disintegrin and metalloproteinase with thrombospondin motifs 17 Human genes 0.000 description 3
- 102100032293 A disintegrin and metalloproteinase with thrombospondin motifs 18 Human genes 0.000 description 3
- 102100032308 A disintegrin and metalloproteinase with thrombospondin motifs 19 Human genes 0.000 description 3
- 102100027399 A disintegrin and metalloproteinase with thrombospondin motifs 2 Human genes 0.000 description 3
- 102100027394 A disintegrin and metalloproteinase with thrombospondin motifs 20 Human genes 0.000 description 3
- 102100027401 A disintegrin and metalloproteinase with thrombospondin motifs 3 Human genes 0.000 description 3
- 102100027400 A disintegrin and metalloproteinase with thrombospondin motifs 4 Human genes 0.000 description 3
- 102100032638 A disintegrin and metalloproteinase with thrombospondin motifs 5 Human genes 0.000 description 3
- 102100032632 A disintegrin and metalloproteinase with thrombospondin motifs 6 Human genes 0.000 description 3
- 102100032639 A disintegrin and metalloproteinase with thrombospondin motifs 7 Human genes 0.000 description 3
- 102100032635 A disintegrin and metalloproteinase with thrombospondin motifs 8 Human genes 0.000 description 3
- 102100032650 A disintegrin and metalloproteinase with thrombospondin motifs 9 Human genes 0.000 description 3
- 108091005662 ADAMTS2 Proteins 0.000 description 3
- 102100034540 Adenomatous polyposis coli protein Human genes 0.000 description 3
- 102100034608 Angiopoietin-2 Human genes 0.000 description 3
- 102000030431 Asparaginyl endopeptidase Human genes 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 3
- 102100032912 CD44 antigen Human genes 0.000 description 3
- 108090000018 Carboxypeptidase D Proteins 0.000 description 3
- 102000000496 Carboxypeptidases A Human genes 0.000 description 3
- 108010080937 Carboxypeptidases A Proteins 0.000 description 3
- 108010022366 Carcinoembryonic Antigen Proteins 0.000 description 3
- 102100025470 Carcinoembryonic antigen-related cell adhesion molecule 8 Human genes 0.000 description 3
- 101710169274 Cathepsin L2 Proteins 0.000 description 3
- 102100026657 Cathepsin Z Human genes 0.000 description 3
- 108010061117 Cathepsin Z Proteins 0.000 description 3
- 102100028757 Chondroitin sulfate proteoglycan 4 Human genes 0.000 description 3
- 108090000317 Chymotrypsin Proteins 0.000 description 3
- 229920002307 Dextran Polymers 0.000 description 3
- 102100034581 Dihydroorotase Human genes 0.000 description 3
- 108091000126 Dihydroorotase Proteins 0.000 description 3
- 101800001224 Disintegrin Proteins 0.000 description 3
- 102100024345 Disintegrin and metalloproteinase domain-containing protein 20 Human genes 0.000 description 3
- 102100024346 Disintegrin and metalloproteinase domain-containing protein 21 Human genes 0.000 description 3
- 102100025984 Disintegrin and metalloproteinase domain-containing protein 30 Human genes 0.000 description 3
- 102100025979 Disintegrin and metalloproteinase domain-containing protein 33 Human genes 0.000 description 3
- 102100023471 E-selectin Human genes 0.000 description 3
- 101150084967 EPCAM gene Proteins 0.000 description 3
- 102100023688 Eotaxin Human genes 0.000 description 3
- 241000206602 Eukaryota Species 0.000 description 3
- 108010057784 Fusion Regulatory Protein-1 Proteins 0.000 description 3
- 102000004130 Fusion Regulatory Protein-1 Human genes 0.000 description 3
- 108090000369 Glutamate Carboxypeptidase II Proteins 0.000 description 3
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 3
- 102100028113 Granulocyte-macrophage colony-stimulating factor receptor subunit alpha Human genes 0.000 description 3
- 108060005986 Granzyme Proteins 0.000 description 3
- 102100028976 HLA class I histocompatibility antigen, B alpha chain Human genes 0.000 description 3
- 108010088729 HLA-A*02:01 antigen Proteins 0.000 description 3
- 108010058607 HLA-B Antigens Proteins 0.000 description 3
- 102000003693 Hedgehog Proteins Human genes 0.000 description 3
- 108090000031 Hedgehog Proteins Proteins 0.000 description 3
- 241000711549 Hepacivirus C Species 0.000 description 3
- 108010007712 Hepatitis A Virus Cellular Receptor 1 Proteins 0.000 description 3
- 241000700721 Hepatitis B virus Species 0.000 description 3
- 102100032813 Hepatocyte growth factor-like protein Human genes 0.000 description 3
- 102100026122 High affinity immunoglobulin gamma Fc receptor I Human genes 0.000 description 3
- 101000798441 Homo sapiens Basigin Proteins 0.000 description 3
- 101000868215 Homo sapiens CD40 ligand Proteins 0.000 description 3
- 101000914324 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 5 Proteins 0.000 description 3
- 101000914320 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 8 Proteins 0.000 description 3
- 101000935040 Homo sapiens Integrin beta-2 Proteins 0.000 description 3
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 3
- 101000878605 Homo sapiens Low affinity immunoglobulin epsilon Fc receptor Proteins 0.000 description 3
- 101001056015 Homo sapiens Mannan-binding lectin serine protease 2 Proteins 0.000 description 3
- 101000627860 Homo sapiens Matrix metalloproteinase-27 Proteins 0.000 description 3
- 101000577540 Homo sapiens Neuropilin-1 Proteins 0.000 description 3
- 101000622137 Homo sapiens P-selectin Proteins 0.000 description 3
- 101000904724 Homo sapiens Transmembrane glycoprotein NMB Proteins 0.000 description 3
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 3
- 102100021496 Insulin-degrading enzyme Human genes 0.000 description 3
- 102100039688 Insulin-like growth factor 1 receptor Human genes 0.000 description 3
- 108090000828 Insulysin Proteins 0.000 description 3
- 102100032818 Integrin alpha-4 Human genes 0.000 description 3
- 102100032817 Integrin alpha-5 Human genes 0.000 description 3
- 102100022339 Integrin alpha-L Human genes 0.000 description 3
- 102100025390 Integrin beta-2 Human genes 0.000 description 3
- 108010064600 Intercellular Adhesion Molecule-3 Proteins 0.000 description 3
- 108010038501 Interleukin-6 Receptors Proteins 0.000 description 3
- 108010014691 Lithostathine Proteins 0.000 description 3
- 102100027361 Lithostathine-1-alpha Human genes 0.000 description 3
- 102100026238 Lymphotoxin-alpha Human genes 0.000 description 3
- 101150014058 MMP1 gene Proteins 0.000 description 3
- 102100026046 Mannan-binding lectin serine protease 2 Human genes 0.000 description 3
- 102000000422 Matrix Metalloproteinase 3 Human genes 0.000 description 3
- 102100024132 Matrix metalloproteinase-27 Human genes 0.000 description 3
- 108090000591 Metallocarboxypeptidase D Proteins 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 108010008707 Mucin-1 Proteins 0.000 description 3
- 208000005647 Mumps Diseases 0.000 description 3
- 102100021850 Nardilysin Human genes 0.000 description 3
- 108090000970 Nardilysin Proteins 0.000 description 3
- 108010025020 Nerve Growth Factor Proteins 0.000 description 3
- 102100032132 Neuroendocrine convertase 1 Human genes 0.000 description 3
- 102000057297 Pepsin A Human genes 0.000 description 3
- 108090000284 Pepsin A Proteins 0.000 description 3
- 102000013566 Plasminogen Human genes 0.000 description 3
- 108010051456 Plasminogen Proteins 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 102100024778 Polyserase-2 Human genes 0.000 description 3
- 101710148859 Polyserase-2 Proteins 0.000 description 3
- 206010060862 Prostate cancer Diseases 0.000 description 3
- 108010025832 RANK Ligand Proteins 0.000 description 3
- 108010029157 Sialic Acid Binding Ig-like Lectin 2 Proteins 0.000 description 3
- 102000004338 Transferrin Human genes 0.000 description 3
- 108090000901 Transferrin Proteins 0.000 description 3
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 3
- 102100033579 Trophoblast glycoprotein Human genes 0.000 description 3
- 102100024586 Tumor necrosis factor ligand superfamily member 14 Human genes 0.000 description 3
- 102100028786 Tumor necrosis factor receptor superfamily member 12A Human genes 0.000 description 3
- 108010066496 Ubiquitin-Specific Proteases Proteins 0.000 description 3
- 102000018390 Ubiquitin-Specific Proteases Human genes 0.000 description 3
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 3
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 3
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 238000001994 activation Methods 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 125000003275 alpha amino acid group Chemical group 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 229940127131 antibody-peptide-conjugate Drugs 0.000 description 3
- 108010055066 asparaginylendopeptidase Proteins 0.000 description 3
- 201000008274 breast adenocarcinoma Diseases 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 3
- 229960002376 chymotrypsin Drugs 0.000 description 3
- 108700004333 collagenase 1 Proteins 0.000 description 3
- 230000021615 conjugation Effects 0.000 description 3
- 235000018417 cysteine Nutrition 0.000 description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 108020001507 fusion proteins Proteins 0.000 description 3
- 102000037865 fusion proteins Human genes 0.000 description 3
- 101150029683 gB gene Proteins 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 230000002101 lytic effect Effects 0.000 description 3
- 210000002540 macrophage Anatomy 0.000 description 3
- 208000010805 mumps infectious disease Diseases 0.000 description 3
- 208000025113 myeloid leukemia Diseases 0.000 description 3
- 210000001672 ovary Anatomy 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000009870 specific binding Effects 0.000 description 3
- 108091007196 stromelysin Proteins 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 210000001550 testis Anatomy 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 239000003053 toxin Substances 0.000 description 3
- 231100000765 toxin Toxicity 0.000 description 3
- 108700012359 toxins Proteins 0.000 description 3
- 239000012581 transferrin Substances 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- 238000002255 vaccination Methods 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- JWDFQMWEFLOOED-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-(pyridin-2-yldisulfanyl)propanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCSSC1=CC=CC=N1 JWDFQMWEFLOOED-UHFFFAOYSA-N 0.000 description 2
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 2
- KPAIBEKNDBAQDX-AKKDPBBWSA-N (4S,5R,6R)-5-amino-2,4-dihydroxy-3-(2-hydroxyacetyl)-6-[(1R,2R)-1,2,3-trihydroxypropyl]oxane-2-carboxylic acid Chemical compound C(CO)(=O)C1C(C(O)=O)(O)O[C@H]([C@@H]([C@H]1O)N)[C@H](O)[C@H](O)CO KPAIBEKNDBAQDX-AKKDPBBWSA-N 0.000 description 2
- 102100035906 (Lyso)-N-acylphosphatidylethanolamine lipase Human genes 0.000 description 2
- 101710164054 (Lyso)-N-acylphosphatidylethanolamine lipase Proteins 0.000 description 2
- 102100035905 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 Human genes 0.000 description 2
- 101710163881 5,6-dihydroxyindole-2-carboxylic acid oxidase Proteins 0.000 description 2
- 101150067423 ADGRG2 gene Proteins 0.000 description 2
- 108091005560 ADGRG3 Proteins 0.000 description 2
- 102100033639 Acetylcholinesterase Human genes 0.000 description 2
- 108010022752 Acetylcholinesterase Proteins 0.000 description 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 2
- 102100032488 Acylamino-acid-releasing enzyme Human genes 0.000 description 2
- 108010061216 Acylaminoacyl-peptidase Proteins 0.000 description 2
- 208000036832 Adenocarcinoma of ovary Diseases 0.000 description 2
- 206010052747 Adenocarcinoma pancreas Diseases 0.000 description 2
- 102100024438 Adhesion G protein-coupled receptor A3 Human genes 0.000 description 2
- 102100032601 Adhesion G protein-coupled receptor B2 Human genes 0.000 description 2
- 101710096307 Adhesion G protein-coupled receptor B2 Proteins 0.000 description 2
- 102100026439 Adhesion G protein-coupled receptor E1 Human genes 0.000 description 2
- 101710096331 Adhesion G protein-coupled receptor E1 Proteins 0.000 description 2
- 102100026402 Adhesion G protein-coupled receptor E2 Human genes 0.000 description 2
- 101710096292 Adhesion G protein-coupled receptor E2 Proteins 0.000 description 2
- 102100026425 Adhesion G protein-coupled receptor E3 Human genes 0.000 description 2
- 102100031933 Adhesion G protein-coupled receptor F5 Human genes 0.000 description 2
- 102100040037 Adhesion G protein-coupled receptor G3 Human genes 0.000 description 2
- 102100036793 Adhesion G protein-coupled receptor L3 Human genes 0.000 description 2
- 102100036792 Adhesion G protein-coupled receptor L4 Human genes 0.000 description 2
- 101710096346 Adhesion G protein-coupled receptor L4 Proteins 0.000 description 2
- 102100026441 Adhesion G-protein coupled receptor D1 Human genes 0.000 description 2
- 102100026443 Adhesion G-protein coupled receptor F1 Human genes 0.000 description 2
- 102100031927 Adhesion G-protein coupled receptor F3 Human genes 0.000 description 2
- 102100031934 Adhesion G-protein coupled receptor G1 Human genes 0.000 description 2
- 102100040036 Adhesion G-protein coupled receptor G4 Human genes 0.000 description 2
- 101710096376 Adhesion G-protein coupled receptor G4 Proteins 0.000 description 2
- 102100040023 Adhesion G-protein coupled receptor G6 Human genes 0.000 description 2
- 102100039732 Adhesion G-protein coupled receptor G7 Human genes 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 2
- 102100039322 Aminopeptidase RNPEPL1 Human genes 0.000 description 2
- 102000004400 Aminopeptidases Human genes 0.000 description 2
- 108090000915 Aminopeptidases Proteins 0.000 description 2
- 101710145634 Antigen 1 Proteins 0.000 description 2
- 102100024624 Arylacetamide deacetylase Human genes 0.000 description 2
- 101710116704 Arylacetamide deacetylase Proteins 0.000 description 2
- 108010018854 Arylformamidase Proteins 0.000 description 2
- 108010023546 Aspartylglucosylaminase Proteins 0.000 description 2
- 108010028006 B-Cell Activating Factor Proteins 0.000 description 2
- 101150089516 BLLF1 gene Proteins 0.000 description 2
- 101150009389 BZLF1 gene Proteins 0.000 description 2
- 108010005785 Beta-aspartyl-peptidase Proteins 0.000 description 2
- 101710149863 C-C chemokine receptor type 4 Proteins 0.000 description 2
- 108010008629 CA-125 Antigen Proteins 0.000 description 2
- 102100024217 CAMPATH-1 antigen Human genes 0.000 description 2
- 108010029697 CD40 Ligand Proteins 0.000 description 2
- 108010065524 CD52 Antigen Proteins 0.000 description 2
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 2
- 102100035680 Cadherin EGF LAG seven-pass G-type receptor 2 Human genes 0.000 description 2
- 101710146247 Cadherin EGF LAG seven-pass G-type receptor 2 Proteins 0.000 description 2
- 101710113083 Carbamoyl-phosphate synthase Proteins 0.000 description 2
- 108010051152 Carboxylesterase Proteins 0.000 description 2
- 102000013392 Carboxylesterase Human genes 0.000 description 2
- 101710117348 Carboxylesterase 1D Proteins 0.000 description 2
- 101710201075 Carboxylesterase 2 Proteins 0.000 description 2
- 102100036808 Carboxylesterase 3 Human genes 0.000 description 2
- 101710201072 Carboxylesterase 3 Proteins 0.000 description 2
- 102100030621 Carboxypeptidase A4 Human genes 0.000 description 2
- 102100026684 Carboxypeptidase O Human genes 0.000 description 2
- 101710082751 Carboxypeptidase S1 homolog A Proteins 0.000 description 2
- 102100021953 Carboxypeptidase Z Human genes 0.000 description 2
- 102100025466 Carcinoembryonic antigen-related cell adhesion molecule 3 Human genes 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 102000011727 Caspases Human genes 0.000 description 2
- 108010076667 Caspases Proteins 0.000 description 2
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 2
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 2
- 108010082548 Chemokine CCL11 Proteins 0.000 description 2
- 102000003914 Cholinesterases Human genes 0.000 description 2
- 108090000322 Cholinesterases Proteins 0.000 description 2
- 101710198480 Clumping factor A Proteins 0.000 description 2
- 102100021864 Cocaine esterase Human genes 0.000 description 2
- 108010048623 Collagen Receptors Proteins 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 102100036966 Dipeptidyl aminopeptidase-like protein 6 Human genes 0.000 description 2
- 102100020751 Dipeptidyl peptidase 2 Human genes 0.000 description 2
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 2
- 102100036968 Dipeptidyl peptidase 8 Human genes 0.000 description 2
- 102100036969 Dipeptidyl peptidase 9 Human genes 0.000 description 2
- 102100025682 Dystroglycan 1 Human genes 0.000 description 2
- 108010071885 Dystroglycans Proteins 0.000 description 2
- 101150059079 EBNA1 gene Proteins 0.000 description 2
- 101150113929 EBNA2 gene Proteins 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 102000005593 Endopeptidases Human genes 0.000 description 2
- 108010059378 Endopeptidases Proteins 0.000 description 2
- 108030001679 Endothelin-converting enzyme 1 Proteins 0.000 description 2
- 102000048186 Endothelin-converting enzyme 1 Human genes 0.000 description 2
- 102100039353 Epoxide hydrolase 3 Human genes 0.000 description 2
- 102000012377 Epoxide hydrolase-like Human genes 0.000 description 2
- 108050002910 Epoxide hydrolase-like Proteins 0.000 description 2
- 108010087819 Fc receptors Proteins 0.000 description 2
- 102000009109 Fc receptors Human genes 0.000 description 2
- 102000004961 Furin Human genes 0.000 description 2
- 108090001126 Furin Proteins 0.000 description 2
- 102100021023 Gamma-glutamyl hydrolase Human genes 0.000 description 2
- 101710107035 Gamma-glutamyltranspeptidase Proteins 0.000 description 2
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 2
- 206010018338 Glioma Diseases 0.000 description 2
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 description 2
- 102100032882 Glucagon-like peptide 1 receptor Human genes 0.000 description 2
- 102100020972 Glutamine amidotransferase-like class 1 domain-containing protein 3, mitochondrial Human genes 0.000 description 2
- 108010058940 Glutamyl Aminopeptidase Proteins 0.000 description 2
- 102000006485 Glutamyl Aminopeptidase Human genes 0.000 description 2
- 102100025527 Glutathione hydrolase light chain 2 Human genes 0.000 description 2
- 101710173228 Glutathione hydrolase proenzyme Proteins 0.000 description 2
- 102100021866 Hepatocyte growth factor Human genes 0.000 description 2
- 101000929840 Homo sapiens 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 Proteins 0.000 description 2
- 101000800023 Homo sapiens 4F2 cell-surface antigen heavy chain Proteins 0.000 description 2
- 101000773083 Homo sapiens 5,6-dihydroxyindole-2-carboxylic acid oxidase Proteins 0.000 description 2
- 101000777636 Homo sapiens ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Proteins 0.000 description 2
- 101000833357 Homo sapiens Adhesion G protein-coupled receptor A3 Proteins 0.000 description 2
- 101000718235 Homo sapiens Adhesion G protein-coupled receptor E3 Proteins 0.000 description 2
- 101000775045 Homo sapiens Adhesion G protein-coupled receptor F5 Proteins 0.000 description 2
- 101000718219 Homo sapiens Adhesion G-protein coupled receptor D1 Proteins 0.000 description 2
- 101000718228 Homo sapiens Adhesion G-protein coupled receptor F1 Proteins 0.000 description 2
- 101000775048 Homo sapiens Adhesion G-protein coupled receptor F3 Proteins 0.000 description 2
- 101000775042 Homo sapiens Adhesion G-protein coupled receptor G1 Proteins 0.000 description 2
- 101000959602 Homo sapiens Adhesion G-protein coupled receptor G6 Proteins 0.000 description 2
- 101000959592 Homo sapiens Adhesion G-protein coupled receptor G7 Proteins 0.000 description 2
- 101000924533 Homo sapiens Angiopoietin-2 Proteins 0.000 description 2
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 description 2
- 101000910852 Homo sapiens Carboxypeptidase O Proteins 0.000 description 2
- 101000914337 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 3 Proteins 0.000 description 2
- 101000914321 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 7 Proteins 0.000 description 2
- 101000916489 Homo sapiens Chondroitin sulfate proteoglycan 4 Proteins 0.000 description 2
- 101000907951 Homo sapiens Chymotrypsin-like elastase family member 3B Proteins 0.000 description 2
- 101000804935 Homo sapiens Dipeptidyl aminopeptidase-like protein 6 Proteins 0.000 description 2
- 101000804947 Homo sapiens Dipeptidyl peptidase 8 Proteins 0.000 description 2
- 101000804945 Homo sapiens Dipeptidyl peptidase 9 Proteins 0.000 description 2
- 101000622123 Homo sapiens E-selectin Proteins 0.000 description 2
- 101000851181 Homo sapiens Epidermal growth factor receptor Proteins 0.000 description 2
- 101000812391 Homo sapiens Epoxide hydrolase 3 Proteins 0.000 description 2
- 101001002170 Homo sapiens Glutamine amidotransferase-like class 1 domain-containing protein 3, mitochondrial Proteins 0.000 description 2
- 101000856496 Homo sapiens Glutathione hydrolase light chain 2 Proteins 0.000 description 2
- 101000916625 Homo sapiens Granulocyte-macrophage colony-stimulating factor receptor subunit alpha Proteins 0.000 description 2
- 101000898034 Homo sapiens Hepatocyte growth factor Proteins 0.000 description 2
- 101000913074 Homo sapiens High affinity immunoglobulin gamma Fc receptor I Proteins 0.000 description 2
- 101000967820 Homo sapiens Inactive dipeptidyl peptidase 10 Proteins 0.000 description 2
- 101001034652 Homo sapiens Insulin-like growth factor 1 receptor Proteins 0.000 description 2
- 101001078133 Homo sapiens Integrin alpha-2 Proteins 0.000 description 2
- 101000994369 Homo sapiens Integrin alpha-5 Proteins 0.000 description 2
- 101000935043 Homo sapiens Integrin beta-1 Proteins 0.000 description 2
- 101000599852 Homo sapiens Intercellular adhesion molecule 1 Proteins 0.000 description 2
- 101001055145 Homo sapiens Interleukin-2 receptor subunit beta Proteins 0.000 description 2
- 101000960936 Homo sapiens Interleukin-5 receptor subunit alpha Proteins 0.000 description 2
- 101001076408 Homo sapiens Interleukin-6 Proteins 0.000 description 2
- 101001008922 Homo sapiens Kallikrein-11 Proteins 0.000 description 2
- 101000764535 Homo sapiens Lymphotoxin-alpha Proteins 0.000 description 2
- 101000764294 Homo sapiens Lymphotoxin-beta Proteins 0.000 description 2
- 101000627851 Homo sapiens Matrix metalloproteinase-23 Proteins 0.000 description 2
- 101000576802 Homo sapiens Mesothelin Proteins 0.000 description 2
- 101001122313 Homo sapiens Metalloendopeptidase OMA1, mitochondrial Proteins 0.000 description 2
- 101001122137 Homo sapiens Olfactory receptor 11H1 Proteins 0.000 description 2
- 101001122134 Homo sapiens Olfactory receptor 11H2 Proteins 0.000 description 2
- 101000594464 Homo sapiens Olfactory receptor 2AP1 Proteins 0.000 description 2
- 101001122441 Homo sapiens Olfactory receptor 4A5 Proteins 0.000 description 2
- 101000721114 Homo sapiens Olfactory receptor 4D10 Proteins 0.000 description 2
- 101001138471 Homo sapiens Olfactory receptor 5H14 Proteins 0.000 description 2
- 101000992272 Homo sapiens Olfactory receptor 5M1 Proteins 0.000 description 2
- 101000598910 Homo sapiens Olfactory receptor 6J1 Proteins 0.000 description 2
- 101000598913 Homo sapiens Olfactory receptor 6K3 Proteins 0.000 description 2
- 101001136034 Homo sapiens Phosphoribosylformylglycinamidine synthase Proteins 0.000 description 2
- 101000730585 Homo sapiens Polycystic kidney disease protein 1-like 2 Proteins 0.000 description 2
- 101000730587 Homo sapiens Polycystic kidney disease protein 1-like 3 Proteins 0.000 description 2
- 101000745667 Homo sapiens Probable serine carboxypeptidase CPVL Proteins 0.000 description 2
- 101001095266 Homo sapiens Prolyl endopeptidase Proteins 0.000 description 2
- 101000684208 Homo sapiens Prolyl endopeptidase FAP Proteins 0.000 description 2
- 101001095240 Homo sapiens Prolyl endopeptidase-like Proteins 0.000 description 2
- 101001072067 Homo sapiens Proprotein convertase subtilisin/kexin type 4 Proteins 0.000 description 2
- 101001098833 Homo sapiens Proprotein convertase subtilisin/kexin type 6 Proteins 0.000 description 2
- 101001105486 Homo sapiens Proteasome subunit alpha type-7 Proteins 0.000 description 2
- 101001136981 Homo sapiens Proteasome subunit beta type-9 Proteins 0.000 description 2
- 101000677768 Homo sapiens Protein ABHD12B Proteins 0.000 description 2
- 101000760638 Homo sapiens Protein ABHD16B Proteins 0.000 description 2
- 101000718237 Homo sapiens Putative adhesion G protein-coupled receptor E4P Proteins 0.000 description 2
- 101000908015 Homo sapiens Putative inactive carboxylesterase 4 Proteins 0.000 description 2
- 101000968736 Homo sapiens Putative olfactory receptor 10D4 Proteins 0.000 description 2
- 101000594444 Homo sapiens Putative olfactory receptor 10J6 Proteins 0.000 description 2
- 101001137083 Homo sapiens Putative olfactory receptor 2W6 Proteins 0.000 description 2
- 101000990748 Homo sapiens Putative olfactory receptor 52L2 Proteins 0.000 description 2
- 101001086356 Homo sapiens Putative olfactory receptor 7A2 Proteins 0.000 description 2
- 101001121746 Homo sapiens Putative olfactory receptor 8G2 Proteins 0.000 description 2
- 101000868152 Homo sapiens Son of sevenless homolog 1 Proteins 0.000 description 2
- 101000801433 Homo sapiens Trophoblast glycoprotein Proteins 0.000 description 2
- 101000847952 Homo sapiens Trypsin-3 Proteins 0.000 description 2
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 2
- 101000830603 Homo sapiens Tumor necrosis factor ligand superfamily member 11 Proteins 0.000 description 2
- 101000830600 Homo sapiens Tumor necrosis factor ligand superfamily member 13 Proteins 0.000 description 2
- 101000851434 Homo sapiens Tumor necrosis factor ligand superfamily member 13B Proteins 0.000 description 2
- 101000648505 Homo sapiens Tumor necrosis factor receptor superfamily member 12A Proteins 0.000 description 2
- 101000808011 Homo sapiens Vascular endothelial growth factor A Proteins 0.000 description 2
- 101000851018 Homo sapiens Vascular endothelial growth factor receptor 1 Proteins 0.000 description 2
- 101000854908 Homo sapiens WD repeat-containing protein 11 Proteins 0.000 description 2
- 108030003252 HtrA2 peptidases Proteins 0.000 description 2
- 241000713887 Human endogenous retrovirus Species 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 102100040449 Inactive dipeptidyl peptidase 10 Human genes 0.000 description 2
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 2
- 102100025305 Integrin alpha-2 Human genes 0.000 description 2
- 102000000507 Integrin alpha2 Human genes 0.000 description 2
- 108010017642 Integrin alpha2beta1 Proteins 0.000 description 2
- 102100025304 Integrin beta-1 Human genes 0.000 description 2
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 2
- 108010038453 Interleukin-2 Receptors Proteins 0.000 description 2
- 102000010789 Interleukin-2 Receptors Human genes 0.000 description 2
- 102100026879 Interleukin-2 receptor subunit beta Human genes 0.000 description 2
- 102000010787 Interleukin-4 Receptors Human genes 0.000 description 2
- 108010038486 Interleukin-4 Receptors Proteins 0.000 description 2
- 102100039881 Interleukin-5 receptor subunit alpha Human genes 0.000 description 2
- 102000010781 Interleukin-6 Receptors Human genes 0.000 description 2
- 102100033903 Isoaspartyl peptidase/L-asparaginase Human genes 0.000 description 2
- 102100027612 Kallikrein-11 Human genes 0.000 description 2
- 102100040621 Kynurenine formamidase Human genes 0.000 description 2
- 102100033467 L-selectin Human genes 0.000 description 2
- 101150113776 LMP1 gene Proteins 0.000 description 2
- 108050008782 Latrophilin-1 Proteins 0.000 description 2
- 108050008761 Latrophilin-2 Proteins 0.000 description 2
- 108050006734 Latrophilin-3 Proteins 0.000 description 2
- 102000003960 Ligases Human genes 0.000 description 2
- 108090000364 Ligases Proteins 0.000 description 2
- 101710128782 Liver carboxylesterase Proteins 0.000 description 2
- 108030000572 Lysosomal Pro-Xaa carboxypeptidases Proteins 0.000 description 2
- 101710196759 Macrophage-stimulating protein receptor Proteins 0.000 description 2
- 102000008990 Mannan-binding lectin-associated serine peptidase 2 Human genes 0.000 description 2
- 108050000952 Mannan-binding lectin-associated serine peptidase 2 Proteins 0.000 description 2
- 102000009112 Mannose-Binding Lectin Human genes 0.000 description 2
- 108010087870 Mannose-Binding Lectin Proteins 0.000 description 2
- 108010091175 Matriptase Proteins 0.000 description 2
- 102400000740 Melanocyte-stimulating hormone alpha Human genes 0.000 description 2
- 101710200814 Melanotropin alpha Proteins 0.000 description 2
- 108030004769 Membrane dipeptidases Proteins 0.000 description 2
- 102000013799 Meprin alpha subunit Human genes 0.000 description 2
- 108050003614 Meprin alpha subunit Proteins 0.000 description 2
- 241000579835 Merops Species 0.000 description 2
- 241001436793 Meru Species 0.000 description 2
- 102100025096 Mesothelin Human genes 0.000 description 2
- 102100027104 Metalloendopeptidase OMA1, mitochondrial Human genes 0.000 description 2
- 108090000192 Methionyl aminopeptidases Proteins 0.000 description 2
- 102100026934 Mitochondrial intermediate peptidase Human genes 0.000 description 2
- 108010047660 Mitochondrial intermediate peptidase Proteins 0.000 description 2
- 108010042046 Mitochondrial processing peptidase Proteins 0.000 description 2
- 101000718239 Mus musculus Adhesion G protein-coupled receptor E4 Proteins 0.000 description 2
- 101000864126 Mus musculus Dipeptidase 2 Proteins 0.000 description 2
- 101000864132 Mus musculus Dipeptidase 3 Proteins 0.000 description 2
- 101000968511 Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) Triacylglycerol lipase Proteins 0.000 description 2
- 102100021003 N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase Human genes 0.000 description 2
- FDJKUWYYUZCUJX-AJKRCSPLSA-N N-glycoloyl-beta-neuraminic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@@H]1O[C@](O)(C(O)=O)C[C@H](O)[C@H]1NC(=O)CO FDJKUWYYUZCUJX-AJKRCSPLSA-N 0.000 description 2
- FDJKUWYYUZCUJX-UHFFFAOYSA-N N-glycolyl-beta-neuraminic acid Natural products OCC(O)C(O)C1OC(O)(C(O)=O)CC(O)C1NC(=O)CO FDJKUWYYUZCUJX-UHFFFAOYSA-N 0.000 description 2
- FDJKUWYYUZCUJX-KVNVFURPSA-N N-glycolylneuraminic acid Chemical compound OC[C@H](O)[C@H](O)[C@@H]1O[C@](O)(C(O)=O)C[C@H](O)[C@H]1NC(=O)CO FDJKUWYYUZCUJX-KVNVFURPSA-N 0.000 description 2
- 108050003738 Neural cell adhesion molecule 1 Proteins 0.000 description 2
- 102100038992 Neuroligin-1 Human genes 0.000 description 2
- 102100034441 Neuroligin-4, X-linked Human genes 0.000 description 2
- 101710083717 Neuroligin-4, X-linked Proteins 0.000 description 2
- 102100034448 Neuroligin-4, Y-linked Human genes 0.000 description 2
- 101710137815 Neuroligin-4, Y-linked Proteins 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 108010077641 Nogo Proteins Proteins 0.000 description 2
- 101710163270 Nuclease Proteins 0.000 description 2
- 102100037589 OX-2 membrane glycoprotein Human genes 0.000 description 2
- 206010061328 Ovarian epithelial cancer Diseases 0.000 description 2
- 102100026305 Ovochymase-1 Human genes 0.000 description 2
- 101710205512 Ovochymase-1 Proteins 0.000 description 2
- 101710167374 Peptidase 1 Proteins 0.000 description 2
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 2
- 241000070023 Phoenicopterus roseus Species 0.000 description 2
- 102100036473 Phosphoribosylformylglycinamidine synthase Human genes 0.000 description 2
- 102100030485 Platelet-derived growth factor receptor alpha Human genes 0.000 description 2
- 102100032597 Polycystic kidney disease protein 1-like 2 Human genes 0.000 description 2
- 102100032598 Polycystic kidney disease protein 1-like 3 Human genes 0.000 description 2
- 102100036143 Polycystin-1 Human genes 0.000 description 2
- 101710146367 Polycystin-1 Proteins 0.000 description 2
- 102100039310 Probable serine carboxypeptidase CPVL Human genes 0.000 description 2
- 108010050808 Procollagen Proteins 0.000 description 2
- 102000056251 Prolyl Oligopeptidases Human genes 0.000 description 2
- 102100037822 Prolyl endopeptidase-like Human genes 0.000 description 2
- 102000004088 Proprotein Convertase 2 Human genes 0.000 description 2
- 108090000545 Proprotein Convertase 2 Proteins 0.000 description 2
- 102000012210 Proprotein Convertase 5 Human genes 0.000 description 2
- 108010022052 Proprotein Convertase 5 Proteins 0.000 description 2
- 102000012343 Proprotein Convertase 9 Human genes 0.000 description 2
- 108010022249 Proprotein Convertase 9 Proteins 0.000 description 2
- 108090000544 Proprotein convertase 1 Proteins 0.000 description 2
- 102100036371 Proprotein convertase subtilisin/kexin type 4 Human genes 0.000 description 2
- 102100038950 Proprotein convertase subtilisin/kexin type 7 Human genes 0.000 description 2
- 101710180647 Proprotein convertase subtilisin/kexin type 7 Proteins 0.000 description 2
- 102100021201 Proteasome subunit alpha type-7 Human genes 0.000 description 2
- 102100035764 Proteasome subunit beta type-9 Human genes 0.000 description 2
- 102100021513 Protein ABHD12B Human genes 0.000 description 2
- 102100024647 Protein ABHD14B Human genes 0.000 description 2
- 101710173275 Protein ABHD14B Proteins 0.000 description 2
- 102100024651 Protein ABHD16B Human genes 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 101000762949 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) Exotoxin A Proteins 0.000 description 2
- 102100026426 Putative adhesion G protein-coupled receptor E4P Human genes 0.000 description 2
- 102100023322 Putative inactive carboxylesterase 4 Human genes 0.000 description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 description 2
- 108010039491 Ricin Proteins 0.000 description 2
- 102100034201 Sclerostin Human genes 0.000 description 2
- 108050006698 Sclerostin Proteins 0.000 description 2
- 102100031070 Serine protease 53 Human genes 0.000 description 2
- 101710197594 Serine protease 53 Proteins 0.000 description 2
- 108010029180 Sialic Acid Binding Ig-like Lectin 3 Proteins 0.000 description 2
- 108010055297 Sterol Esterase Proteins 0.000 description 2
- 102000000019 Sterol Esterase Human genes 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 229940100514 Syk tyrosine kinase inhibitor Drugs 0.000 description 2
- 102100025131 T-cell differentiation antigen CD6 Human genes 0.000 description 2
- 101150057140 TACSTD1 gene Proteins 0.000 description 2
- 108091007178 TNFRSF10A Proteins 0.000 description 2
- 208000024313 Testicular Neoplasms Diseases 0.000 description 2
- 102000005488 Thioesterase Human genes 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- 102100040483 Threonine aspartase 1 Human genes 0.000 description 2
- 108050009080 Threonine aspartase 1 Proteins 0.000 description 2
- 102100033504 Thyroglobulin Human genes 0.000 description 2
- 108010034949 Thyroglobulin Proteins 0.000 description 2
- 108010033576 Transferrin Receptors Proteins 0.000 description 2
- 102000011117 Transforming Growth Factor beta2 Human genes 0.000 description 2
- 101800000304 Transforming growth factor beta-2 Proteins 0.000 description 2
- 108010039203 Tripeptidyl-Peptidase 1 Proteins 0.000 description 2
- 102100034197 Tripeptidyl-peptidase 1 Human genes 0.000 description 2
- 102100040411 Tripeptidyl-peptidase 2 Human genes 0.000 description 2
- 102100034396 Trypsin-3 Human genes 0.000 description 2
- 108010065158 Tumor Necrosis Factor Ligand Superfamily Member 14 Proteins 0.000 description 2
- 102100024585 Tumor necrosis factor ligand superfamily member 13 Human genes 0.000 description 2
- 102220501737 Ubiquitin-like modifier-activating enzyme 1_M67A_mutation Human genes 0.000 description 2
- 108091008605 VEGF receptors Proteins 0.000 description 2
- 102100025139 Valacyclovir hydrolase Human genes 0.000 description 2
- 101710130607 Valacyclovir hydrolase Proteins 0.000 description 2
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 2
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 2
- 108010034265 Vascular Endothelial Growth Factor Receptors Proteins 0.000 description 2
- 102100035071 Vimentin Human genes 0.000 description 2
- 108010065472 Vimentin Proteins 0.000 description 2
- 102100020705 WD repeat-containing protein 11 Human genes 0.000 description 2
- 206010049644 Williams syndrome Diseases 0.000 description 2
- 201000001305 Williams-Beuren syndrome Diseases 0.000 description 2
- 229940022698 acetylcholinesterase Drugs 0.000 description 2
- 108010023082 activin A Proteins 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 230000000735 allogeneic effect Effects 0.000 description 2
- 102000013529 alpha-Fetoproteins Human genes 0.000 description 2
- 108010026331 alpha-Fetoproteins Proteins 0.000 description 2
- 210000002203 alpha-beta t lymphocyte Anatomy 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 108010064397 amyloid beta-protein (1-40) Proteins 0.000 description 2
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 108010087173 bile salt-stimulated lipase Proteins 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000000601 blood cell Anatomy 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- 201000008275 breast carcinoma Diseases 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 230000005859 cell recognition Effects 0.000 description 2
- 229940106189 ceramide Drugs 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940048961 cholinesterase Drugs 0.000 description 2
- 239000010415 colloidal nanoparticle Substances 0.000 description 2
- 201000010989 colorectal carcinoma Diseases 0.000 description 2
- 230000004540 complement-dependent cytotoxicity Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 108010021994 cytomegalovirus matrix protein 65kDa Proteins 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 108090000212 dipeptidyl peptidase II Proteins 0.000 description 2
- 238000000375 direct analysis in real time Methods 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 238000012063 dual-affinity re-targeting Methods 0.000 description 2
- 108010011867 ecallantide Proteins 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 2
- 210000003722 extracellular fluid Anatomy 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 108010072257 fibroblast activation protein alpha Proteins 0.000 description 2
- 230000003176 fibrotic effect Effects 0.000 description 2
- 108010062699 gamma-Glutamyl Hydrolase Proteins 0.000 description 2
- 150000002270 gangliosides Chemical class 0.000 description 2
- 238000010353 genetic engineering Methods 0.000 description 2
- 108010065889 glycyl-leucyl-cysteinyl-threonyl-leucyl-valyl-alanyl-methionyl-leucine Proteins 0.000 description 2
- 210000003714 granulocyte Anatomy 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 210000002443 helper t lymphocyte Anatomy 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 210000003630 histaminocyte Anatomy 0.000 description 2
- 210000004408 hybridoma Anatomy 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 229940127121 immunoconjugate Drugs 0.000 description 2
- 238000003364 immunohistochemistry Methods 0.000 description 2
- 239000002955 immunomodulating agent Substances 0.000 description 2
- 230000001024 immunotherapeutic effect Effects 0.000 description 2
- 239000012678 infectious agent Substances 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- NUHSROFQTUXZQQ-UHFFFAOYSA-N isopentenyl diphosphate Chemical compound CC(=C)CCO[P@](O)(=O)OP(O)(O)=O NUHSROFQTUXZQQ-UHFFFAOYSA-N 0.000 description 2
- VBGWSQKGUZHFPS-VGMMZINCSA-N kalbitor Chemical compound C([C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]2C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=3C=CC=CC=3)C(=O)N[C@H](C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)NCC(=O)NCC(=O)N[C@H]3CSSC[C@H](NC(=O)[C@@H]4CCCN4C(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CO)NC(=O)[C@H](CC=4NC=NC=4)NC(=O)[C@H](CCSC)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(O)=O)CSSC[C@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC3=O)CSSC2)C(=O)N[C@@H]([C@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=2NC=NC=2)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N1)[C@@H](C)CC)[C@H](C)O)=O)[C@@H](C)CC)C1=CC=CC=C1 VBGWSQKGUZHFPS-VGMMZINCSA-N 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 108010053292 macrophage stimulating protein Proteins 0.000 description 2
- 108010090530 metallocarboxypeptidase Z Proteins 0.000 description 2
- 230000002438 mitochondrial effect Effects 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 229940053128 nerve growth factor Drugs 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 108090001100 neuroligin 1 Proteins 0.000 description 2
- 108090001075 neuroligin 2 Proteins 0.000 description 2
- 102000004872 neuroligin 2 Human genes 0.000 description 2
- 108090001073 neuroligin 3 Proteins 0.000 description 2
- 102000004871 neuroligin 3 Human genes 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 238000011580 nude mouse model Methods 0.000 description 2
- 208000013371 ovarian adenocarcinoma Diseases 0.000 description 2
- 201000006588 ovary adenocarcinoma Diseases 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 201000002094 pancreatic adenocarcinoma Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 229940111202 pepsin Drugs 0.000 description 2
- 239000000816 peptidomimetic Substances 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 238000002823 phage display Methods 0.000 description 2
- 230000003169 placental effect Effects 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 210000004986 primary T-cell Anatomy 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 201000001514 prostate carcinoma Diseases 0.000 description 2
- 230000017854 proteolysis Effects 0.000 description 2
- 230000002797 proteolythic effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000002702 ribosome display Methods 0.000 description 2
- 102220215708 rs373718658 Human genes 0.000 description 2
- 108010093322 s-formylglutathione hydrolase Proteins 0.000 description 2
- 102000028528 s-formylglutathione hydrolase Human genes 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 238000012289 standard assay Methods 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 230000002381 testicular Effects 0.000 description 2
- 108020002982 thioesterase Proteins 0.000 description 2
- 210000001541 thymus gland Anatomy 0.000 description 2
- 229960002175 thyroglobulin Drugs 0.000 description 2
- 210000001685 thyroid gland Anatomy 0.000 description 2
- 229940072041 transforming growth factor beta 2 Drugs 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 108010039189 tripeptidyl-peptidase 2 Proteins 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 210000005048 vimentin Anatomy 0.000 description 2
- LLXVXPPXELIDGQ-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-(2,5-dioxopyrrol-1-yl)benzoate Chemical compound C=1C=CC(N2C(C=CC2=O)=O)=CC=1C(=O)ON1C(=O)CCC1=O LLXVXPPXELIDGQ-UHFFFAOYSA-N 0.000 description 1
- FFILOTSTFMXQJC-QCFYAKGBSA-N (2r,4r,5s,6s)-2-[3-[(2s,3s,4r,6s)-6-[(2s,3r,4r,5s,6r)-5-[(2s,3r,4r,5r,6r)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-2-[(2r,3s,4r,5r,6r)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(e)-3-hydroxy-2-(octadecanoylamino)octadec-4-enoxy]oxan-3-yl]oxy-3-hy Chemical compound O[C@@H]1[C@@H](O)[C@H](OCC(NC(=O)CCCCCCCCCCCCCCCCC)C(O)\C=C\CCCCCCCCCCCCC)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@]2(O[C@@H]([C@@H](N)[C@H](O)C2)C(O)C(O)CO[C@]2(O[C@@H]([C@@H](N)[C@H](O)C2)C(O)C(O)CO)C(O)=O)C(O)=O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](CO)O1 FFILOTSTFMXQJC-QCFYAKGBSA-N 0.000 description 1
- LAQPKDLYOBZWBT-NYLDSJSYSA-N (2s,4s,5r,6r)-5-acetamido-2-{[(2s,3r,4s,5s,6r)-2-{[(2r,3r,4r,5r)-5-acetamido-1,2-dihydroxy-6-oxo-4-{[(2s,3s,4r,5s,6s)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxy}hexan-3-yl]oxy}-3,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy}-4-hydroxy-6-[(1r,2r)-1,2,3-trihydrox Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]([C@@H](NC(C)=O)C=O)[C@@H]([C@H](O)CO)O[C@H]1[C@H](O)[C@@H](O[C@]2(O[C@H]([C@H](NC(C)=O)[C@@H](O)C2)[C@H](O)[C@H](O)CO)C(O)=O)[C@@H](O)[C@@H](CO)O1 LAQPKDLYOBZWBT-NYLDSJSYSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- XQUPVDVFXZDTLT-UHFFFAOYSA-N 1-[4-[[4-(2,5-dioxopyrrol-1-yl)phenyl]methyl]phenyl]pyrrole-2,5-dione Chemical compound O=C1C=CC(=O)N1C(C=C1)=CC=C1CC1=CC=C(N2C(C=CC2=O)=O)C=C1 XQUPVDVFXZDTLT-UHFFFAOYSA-N 0.000 description 1
- QZDDFQLIQRYMBV-UHFFFAOYSA-N 2-[3-nitro-2-(2-nitrophenyl)-4-oxochromen-8-yl]acetic acid Chemical compound OC(=O)CC1=CC=CC(C(C=2[N+]([O-])=O)=O)=C1OC=2C1=CC=CC=C1[N+]([O-])=O QZDDFQLIQRYMBV-UHFFFAOYSA-N 0.000 description 1
- KZMAWJRXKGLWGS-UHFFFAOYSA-N 2-chloro-n-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-n-(3-methoxypropyl)acetamide Chemical compound S1C(N(C(=O)CCl)CCCOC)=NC(C=2C=CC(OC)=CC=2)=C1 KZMAWJRXKGLWGS-UHFFFAOYSA-N 0.000 description 1
- 102100036657 26S proteasome non-ATPase regulatory subunit 7 Human genes 0.000 description 1
- 101710091322 26S proteasome non-ATPase regulatory subunit 7 Proteins 0.000 description 1
- MWZTVLNYXAKUKY-LBEKAKSKSA-N 4-hydroxy-N-[2-[(1R,13S)-3-methyl-8-oxo-11-azatetracyclo[8.4.0.01,13.02,7]tetradeca-2,4,6,9-tetraene-11-carbonyl]imidazo[1,2-a]pyridin-6-yl]benzamide Chemical compound C=1([C@]23C[C@@H]3C3)C(C)=CC=CC=1C(=O)C=C2N3C(=O)C(N=C1C=C2)=CN1C=C2NC(=O)C1=CC=C(O)C=C1 MWZTVLNYXAKUKY-LBEKAKSKSA-N 0.000 description 1
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
- YSFGBPCBPNVLOK-UHFFFAOYSA-N 6-hydroxy-2-methylhex-2-enamide Chemical compound NC(=O)C(C)=CCCCO YSFGBPCBPNVLOK-UHFFFAOYSA-N 0.000 description 1
- ULGJWNIHLSLQPZ-UHFFFAOYSA-N 7-[(6,8-dichloro-1,2,3,4-tetrahydroacridin-9-yl)amino]-n-[2-(1h-indol-3-yl)ethyl]heptanamide Chemical compound C1CCCC2=NC3=CC(Cl)=CC(Cl)=C3C(NCCCCCCC(=O)NCCC=3C4=CC=CC=C4NC=3)=C21 ULGJWNIHLSLQPZ-UHFFFAOYSA-N 0.000 description 1
- BSFODEXXVBBYOC-UHFFFAOYSA-N 8-[4-(dimethylamino)butan-2-ylamino]quinolin-6-ol Chemical compound C1=CN=C2C(NC(CCN(C)C)C)=CC(O)=CC2=C1 BSFODEXXVBBYOC-UHFFFAOYSA-N 0.000 description 1
- 102100026007 ADAM DEC1 Human genes 0.000 description 1
- 108010027122 ADP-ribosyl Cyclase 1 Proteins 0.000 description 1
- 108050008264 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Proteins 0.000 description 1
- 102100034215 AFG3-like protein 2 Human genes 0.000 description 1
- 101710135983 AFG3-like protein 2 Proteins 0.000 description 1
- 101150034533 ATIC gene Proteins 0.000 description 1
- 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 description 1
- 108020005296 Acid Ceramidase Proteins 0.000 description 1
- 102100024005 Acid ceramidase Human genes 0.000 description 1
- 102100026041 Acrosin Human genes 0.000 description 1
- 108090000107 Acrosin Proteins 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 102100024394 Adipocyte enhancer-binding protein 1 Human genes 0.000 description 1
- 101710105604 Adipocyte enhancer-binding protein 1 Proteins 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 102100035248 Alpha-(1,3)-fucosyltransferase 4 Human genes 0.000 description 1
- 102100039239 Amidophosphoribosyltransferase Human genes 0.000 description 1
- 108010039224 Amidophosphoribosyltransferase Proteins 0.000 description 1
- 102100032126 Aminopeptidase B Human genes 0.000 description 1
- 102100022749 Aminopeptidase N Human genes 0.000 description 1
- 102100040141 Aminopeptidase O Human genes 0.000 description 1
- 108050008333 Aminopeptidase O Proteins 0.000 description 1
- 101710190488 Aminopeptidase P1 Proteins 0.000 description 1
- 101710190490 Aminopeptidase P2 Proteins 0.000 description 1
- 102100040181 Aminopeptidase Q Human genes 0.000 description 1
- 101710099478 Aminopeptidase Q Proteins 0.000 description 1
- 108010048036 Angiopoietin-2 Proteins 0.000 description 1
- 102100035765 Angiotensin-converting enzyme 2 Human genes 0.000 description 1
- 108090000975 Angiotensin-converting enzyme 2 Proteins 0.000 description 1
- 102000007592 Apolipoproteins Human genes 0.000 description 1
- 108010071619 Apolipoproteins Proteins 0.000 description 1
- 101001005269 Arabidopsis thaliana Ceramide synthase 1 LOH3 Proteins 0.000 description 1
- 101001005312 Arabidopsis thaliana Ceramide synthase LOH1 Proteins 0.000 description 1
- 101100067974 Arabidopsis thaliana POP2 gene Proteins 0.000 description 1
- 102100040176 Archaemetzincin-1 Human genes 0.000 description 1
- 102100040158 Archaemetzincin-2 Human genes 0.000 description 1
- 102100023927 Asparagine synthetase [glutamine-hydrolyzing] Human genes 0.000 description 1
- 108010070255 Aspartate-ammonia ligase Proteins 0.000 description 1
- 102100027710 Astacin-like metalloendopeptidase Human genes 0.000 description 1
- 101710166179 Astacin-like metalloendopeptidase Proteins 0.000 description 1
- 102100021321 Ataxin-3 Human genes 0.000 description 1
- 108010032947 Ataxin-3 Proteins 0.000 description 1
- 102100021301 Ataxin-3-like protein Human genes 0.000 description 1
- 102100037293 Atrial natriuretic peptide-converting enzyme Human genes 0.000 description 1
- 101710133555 Atrial natriuretic peptide-converting enzyme Proteins 0.000 description 1
- 102000019238 Autophagin-2 Human genes 0.000 description 1
- 108050006537 Autophagin-2 Proteins 0.000 description 1
- 102100030009 Azurocidin Human genes 0.000 description 1
- 101710154607 Azurocidin Proteins 0.000 description 1
- 101710187595 B-cell receptor CD22 Proteins 0.000 description 1
- 101150013616 BHRF1 gene Proteins 0.000 description 1
- 101150062763 BMRF1 gene Proteins 0.000 description 1
- 101150002613 BRCC3 gene Proteins 0.000 description 1
- 101150078891 BRLF1 gene Proteins 0.000 description 1
- 108010064528 Basigin Proteins 0.000 description 1
- 101150067964 BcRF1 gene Proteins 0.000 description 1
- 101710129634 Beta-nerve growth factor Proteins 0.000 description 1
- 102100021257 Beta-secretase 1 Human genes 0.000 description 1
- 101710150192 Beta-secretase 1 Proteins 0.000 description 1
- 102100021277 Beta-secretase 2 Human genes 0.000 description 1
- 101710150190 Beta-secretase 2 Proteins 0.000 description 1
- 108010025544 Bleomycin hydrolase Proteins 0.000 description 1
- 102100027058 Bleomycin hydrolase Human genes 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- 101000627848 Bos taurus Matrix metalloproteinase-23 Proteins 0.000 description 1
- 101000655894 Bos taurus Serine protease 1 Proteins 0.000 description 1
- 108010075254 C-Peptide Proteins 0.000 description 1
- 102000007269 CA-125 Antigen Human genes 0.000 description 1
- 102100025752 CASP8 and FADD-like apoptosis regulator Human genes 0.000 description 1
- 108700013048 CCL2 Proteins 0.000 description 1
- 108010049990 CD13 Antigens Proteins 0.000 description 1
- 108010046080 CD27 Ligand Proteins 0.000 description 1
- 108010070033 COP9 Signalosome Complex Proteins 0.000 description 1
- 102100028372 COP9 signalosome complex subunit 6 Human genes 0.000 description 1
- 101150010802 CVC2 gene Proteins 0.000 description 1
- 101150108228 CYLD gene Proteins 0.000 description 1
- 101100123850 Caenorhabditis elegans her-1 gene Proteins 0.000 description 1
- 102000003895 Calpain-1 Human genes 0.000 description 1
- 108090000236 Calpain-1 Proteins 0.000 description 1
- 102100025465 Calpain-10 Human genes 0.000 description 1
- 108090000451 Calpain-10 Proteins 0.000 description 1
- 102100025456 Calpain-11 Human genes 0.000 description 1
- 101710165505 Calpain-11 Proteins 0.000 description 1
- 102100025462 Calpain-12 Human genes 0.000 description 1
- 108050003161 Calpain-12 Proteins 0.000 description 1
- 102000014271 Calpain-13 Human genes 0.000 description 1
- 108050003159 Calpain-13 Proteins 0.000 description 1
- 102100025871 Calpain-14 Human genes 0.000 description 1
- 101710165502 Calpain-14 Proteins 0.000 description 1
- 102100025168 Calpain-15 Human genes 0.000 description 1
- 101710165503 Calpain-15 Proteins 0.000 description 1
- 102000003900 Calpain-2 Human genes 0.000 description 1
- 108090000232 Calpain-2 Proteins 0.000 description 1
- 102000046744 Calpain-3 Human genes 0.000 description 1
- 108030001375 Calpain-3 Proteins 0.000 description 1
- 102100030006 Calpain-5 Human genes 0.000 description 1
- 101710099825 Calpain-5 Proteins 0.000 description 1
- 102100030005 Calpain-6 Human genes 0.000 description 1
- 102000014273 Calpain-8 Human genes 0.000 description 1
- 108050003158 Calpain-8 Proteins 0.000 description 1
- 102000045505 Calpain-9 Human genes 0.000 description 1
- 101710132601 Capsid protein Proteins 0.000 description 1
- 101710097783 Carboxypeptidase A4 Proteins 0.000 description 1
- 102100026793 Carboxypeptidase A6 Human genes 0.000 description 1
- 108700001208 Carboxypeptidase A6 Proteins 0.000 description 1
- 102000003670 Carboxypeptidase B Human genes 0.000 description 1
- 108090000087 Carboxypeptidase B Proteins 0.000 description 1
- 102000003847 Carboxypeptidase B2 Human genes 0.000 description 1
- 108090000201 Carboxypeptidase B2 Proteins 0.000 description 1
- 102100032407 Carboxypeptidase D Human genes 0.000 description 1
- 102100032378 Carboxypeptidase E Human genes 0.000 description 1
- 108010058255 Carboxypeptidase H Proteins 0.000 description 1
- 108090000007 Carboxypeptidase M Proteins 0.000 description 1
- 102100032936 Carboxypeptidase M Human genes 0.000 description 1
- 102220571122 Carboxypeptidase M_M4S_mutation Human genes 0.000 description 1
- 102100026679 Carboxypeptidase Q Human genes 0.000 description 1
- 101710093167 Carboxypeptidase Q Proteins 0.000 description 1
- 102000005367 Carboxypeptidases Human genes 0.000 description 1
- 108010006303 Carboxypeptidases Proteins 0.000 description 1
- 102100025473 Carcinoembryonic antigen-related cell adhesion molecule 6 Human genes 0.000 description 1
- QRYRORQUOLYVBU-VBKZILBWSA-N Carnosic acid Natural products CC([C@@H]1CC2)(C)CCC[C@]1(C(O)=O)C1=C2C=C(C(C)C)C(O)=C1O QRYRORQUOLYVBU-VBKZILBWSA-N 0.000 description 1
- 108010087806 Carnosine Proteins 0.000 description 1
- 108090000397 Caspase 3 Proteins 0.000 description 1
- 102000004018 Caspase 6 Human genes 0.000 description 1
- 108090000425 Caspase 6 Proteins 0.000 description 1
- 108090000567 Caspase 7 Proteins 0.000 description 1
- 102100035904 Caspase-1 Human genes 0.000 description 1
- 108090000426 Caspase-1 Proteins 0.000 description 1
- 102000004068 Caspase-10 Human genes 0.000 description 1
- 108090000572 Caspase-10 Proteins 0.000 description 1
- 102000004066 Caspase-12 Human genes 0.000 description 1
- 108090000570 Caspase-12 Proteins 0.000 description 1
- 102000004958 Caspase-14 Human genes 0.000 description 1
- 108090001132 Caspase-14 Proteins 0.000 description 1
- 102100032616 Caspase-2 Human genes 0.000 description 1
- 108090000552 Caspase-2 Proteins 0.000 description 1
- 102100029855 Caspase-3 Human genes 0.000 description 1
- 102100025597 Caspase-4 Human genes 0.000 description 1
- 101710090338 Caspase-4 Proteins 0.000 description 1
- 102100038916 Caspase-5 Human genes 0.000 description 1
- 101710090333 Caspase-5 Proteins 0.000 description 1
- 102100038902 Caspase-7 Human genes 0.000 description 1
- 102100026548 Caspase-8 Human genes 0.000 description 1
- 108090000538 Caspase-8 Proteins 0.000 description 1
- 102100026550 Caspase-9 Human genes 0.000 description 1
- 108090000566 Caspase-9 Proteins 0.000 description 1
- 101000894568 Catharanthus roseus Catharanthine synthase Proteins 0.000 description 1
- 102000003902 Cathepsin C Human genes 0.000 description 1
- 108090000267 Cathepsin C Proteins 0.000 description 1
- 101710178430 Cathepsin L-like Proteins 0.000 description 1
- 102100024046 Cell adhesion molecule 3 Human genes 0.000 description 1
- 101710197433 Cell adhesion molecule 3 Proteins 0.000 description 1
- 241000251556 Chordata Species 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- 102100024539 Chymase Human genes 0.000 description 1
- 108090000227 Chymases Proteins 0.000 description 1
- 108090000205 Chymotrypsin C Proteins 0.000 description 1
- 102100039511 Chymotrypsin-C Human genes 0.000 description 1
- 102100023338 Chymotrypsin-like elastase family member 2B Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 1
- 108010078015 Complement C3b Proteins 0.000 description 1
- 108090000044 Complement Factor I Proteins 0.000 description 1
- 102000003712 Complement factor B Human genes 0.000 description 1
- 108090000056 Complement factor B Proteins 0.000 description 1
- 102000003706 Complement factor D Human genes 0.000 description 1
- 108090000059 Complement factor D Proteins 0.000 description 1
- 102100035431 Complement factor I Human genes 0.000 description 1
- 101710110138 Cysteine protease ATG4B Proteins 0.000 description 1
- 102100021903 Cysteine protease ATG4B Human genes 0.000 description 1
- 108050001835 Cysteine protease ATG4C Proteins 0.000 description 1
- 102100021902 Cysteine protease ATG4C Human genes 0.000 description 1
- 101710110135 Cysteine protease ATG4D Proteins 0.000 description 1
- 102100027713 Cysteine protease ATG4D Human genes 0.000 description 1
- 108091000069 Cystinyl Aminopeptidase Proteins 0.000 description 1
- 102000030900 Cystinyl aminopeptidase Human genes 0.000 description 1
- 102100039924 Cytochrome b-c1 complex subunit 1, mitochondrial Human genes 0.000 description 1
- 102100039441 Cytochrome b-c1 complex subunit 2, mitochondrial Human genes 0.000 description 1
- 108030000958 Cytosol alanyl aminopeptidases Proteins 0.000 description 1
- 102100035027 Cytosolic carboxypeptidase 1 Human genes 0.000 description 1
- 101710141374 Cytosolic carboxypeptidase 1 Proteins 0.000 description 1
- 102100025721 Cytosolic carboxypeptidase 2 Human genes 0.000 description 1
- 101710141380 Cytosolic carboxypeptidase 2 Proteins 0.000 description 1
- 102100025707 Cytosolic carboxypeptidase 3 Human genes 0.000 description 1
- 101710141379 Cytosolic carboxypeptidase 3 Proteins 0.000 description 1
- 102100032406 Cytosolic carboxypeptidase 6 Human genes 0.000 description 1
- 101710141298 Cytosolic carboxypeptidase 6 Proteins 0.000 description 1
- 102100025717 Cytosolic carboxypeptidase-like protein 5 Human genes 0.000 description 1
- 101710178689 Cytosolic carboxypeptidase-like protein 5 Proteins 0.000 description 1
- 102100031007 Cytosolic non-specific dipeptidase Human genes 0.000 description 1
- 125000000030 D-alanine group Chemical group [H]N([H])[C@](C([H])([H])[H])(C(=O)[*])[H] 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- 101150026402 DBP gene Proteins 0.000 description 1
- 101000777158 Danio rerio Ubiquitin carboxyl-terminal hydrolase 45 Proteins 0.000 description 1
- 102100035091 Deubiquitinase MYSM1 Human genes 0.000 description 1
- 102000001477 Deubiquitinating Enzymes Human genes 0.000 description 1
- 108010093668 Deubiquitinating Enzymes Proteins 0.000 description 1
- 102100023526 Deubiquitinating protein VCPIP1 Human genes 0.000 description 1
- 208000002699 Digestive System Neoplasms Diseases 0.000 description 1
- 102100036238 Dihydropyrimidinase Human genes 0.000 description 1
- 102000012122 Dihydropyrimidinase-related protein 1 Human genes 0.000 description 1
- 108050002656 Dihydropyrimidinase-related protein 1 Proteins 0.000 description 1
- 102000011972 Dihydropyrimidinase-related protein 2 Human genes 0.000 description 1
- 102100024425 Dihydropyrimidinase-related protein 3 Human genes 0.000 description 1
- 108050002650 Dihydropyrimidinase-related protein 3 Proteins 0.000 description 1
- 102000011993 Dihydropyrimidinase-related protein 4 Human genes 0.000 description 1
- 108050002475 Dihydropyrimidinase-related protein 4 Proteins 0.000 description 1
- 102000012120 Dihydropyrimidinase-related protein 5 Human genes 0.000 description 1
- 108050002654 Dihydropyrimidinase-related protein 5 Proteins 0.000 description 1
- 108090001081 Dipeptidases Proteins 0.000 description 1
- 102000004860 Dipeptidases Human genes 0.000 description 1
- 102100020750 Dipeptidyl peptidase 3 Human genes 0.000 description 1
- 102000016607 Diphtheria Toxin Human genes 0.000 description 1
- 108010053187 Diphtheria Toxin Proteins 0.000 description 1
- 102100025978 Disintegrin and metalloproteinase domain-containing protein 32 Human genes 0.000 description 1
- 108010024212 E-Selectin Proteins 0.000 description 1
- 108700036002 EC 3.4.21.69 Proteins 0.000 description 1
- 229940084577 EGFR agonist Drugs 0.000 description 1
- 102000012804 EPCAM Human genes 0.000 description 1
- 101150079262 ERMP1 gene Proteins 0.000 description 1
- 102100025137 Early activation antigen CD69 Human genes 0.000 description 1
- 102000015782 Electron Transport Complex III Human genes 0.000 description 1
- 108010024882 Electron Transport Complex III Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102100021598 Endoplasmic reticulum aminopeptidase 1 Human genes 0.000 description 1
- 101710168245 Endoplasmic reticulum aminopeptidase 1 Proteins 0.000 description 1
- 102100021597 Endoplasmic reticulum aminopeptidase 2 Human genes 0.000 description 1
- 102100029727 Enteropeptidase Human genes 0.000 description 1
- 108010013369 Enteropeptidase Proteins 0.000 description 1
- 101710181478 Envelope glycoprotein GP350 Proteins 0.000 description 1
- 102100030323 Epigen Human genes 0.000 description 1
- 108010016906 Epigen Proteins 0.000 description 1
- 101710147543 Epstein-Barr nuclear antigen leader protein Proteins 0.000 description 1
- 101100381651 Epstein-Barr virus (strain B95-8) BILF2 gene Proteins 0.000 description 1
- 108010069621 Epstein-Barr virus EBV-associated membrane antigen Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 102100034255 Eukaryotic translation initiation factor 3 subunit F Human genes 0.000 description 1
- 101710109032 Eukaryotic translation initiation factor 3 subunit F Proteins 0.000 description 1
- 102100025637 FACT complex subunit SPT16 Human genes 0.000 description 1
- 101710104971 FACT complex subunit SPT16 Proteins 0.000 description 1
- 108010048049 Factor IXa Proteins 0.000 description 1
- 108010071241 Factor XIIa Proteins 0.000 description 1
- 108010080805 Factor XIa Proteins 0.000 description 1
- 108010074860 Factor Xa Proteins 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 108010012088 Fibrinogen Receptors Proteins 0.000 description 1
- 102100037362 Fibronectin Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- 102100020715 Fms-related tyrosine kinase 3 ligand protein Human genes 0.000 description 1
- 101710162577 Fms-related tyrosine kinase 3 ligand protein Proteins 0.000 description 1
- 102100035139 Folate receptor alpha Human genes 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 102100030875 Gastricsin Human genes 0.000 description 1
- 108090001072 Gastricsin Proteins 0.000 description 1
- 102100033429 Glutamine-fructose-6-phosphate aminotransferase [isomerizing] 1 Human genes 0.000 description 1
- 101710165608 Glutamine-fructose-6-phosphate aminotransferase [isomerizing] 1 Proteins 0.000 description 1
- 102000004894 Glutamine-fructose-6-phosphate transaminase (isomerizing) Human genes 0.000 description 1
- 108090001031 Glutamine-fructose-6-phosphate transaminase (isomerizing) Proteins 0.000 description 1
- 108030000059 Gly-Xaa carboxypeptidases Proteins 0.000 description 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- 108010086677 Gonadotropins Proteins 0.000 description 1
- 102000006771 Gonadotropins Human genes 0.000 description 1
- 101710108699 Granulocyte-macrophage colony-stimulating factor receptor subunit alpha Proteins 0.000 description 1
- 102100038393 Granzyme H Human genes 0.000 description 1
- 101710113220 Granzyme H Proteins 0.000 description 1
- 108050003624 Granzyme M Proteins 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 108050006583 Growth/differentiation factor 8 Proteins 0.000 description 1
- 108010012029 Guanine Deaminase Proteins 0.000 description 1
- 102000013587 Guanine deaminase Human genes 0.000 description 1
- 108010043026 HGF activator Proteins 0.000 description 1
- 108091008603 HGF receptors Proteins 0.000 description 1
- 102100028971 HLA class I histocompatibility antigen, C alpha chain Human genes 0.000 description 1
- 102100036242 HLA class II histocompatibility antigen, DQ alpha 2 chain Human genes 0.000 description 1
- 108010052199 HLA-C Antigens Proteins 0.000 description 1
- 108010010378 HLA-DP Antigens Proteins 0.000 description 1
- 102000015789 HLA-DP Antigens Human genes 0.000 description 1
- 108010062347 HLA-DQ Antigens Proteins 0.000 description 1
- 108010058597 HLA-DR Antigens Proteins 0.000 description 1
- 102000006354 HLA-DR Antigens Human genes 0.000 description 1
- 108010053491 HLA-DR beta-Chains Proteins 0.000 description 1
- 108010036449 HLA-DR10 antigen Proteins 0.000 description 1
- 108010001041 HLA-DR7 Antigen Proteins 0.000 description 1
- 102100027772 Haptoglobin-related protein Human genes 0.000 description 1
- 101710122541 Haptoglobin-related protein Proteins 0.000 description 1
- 101710114832 Heat shock protein 90 homolog Proteins 0.000 description 1
- 241000700739 Hepadnaviridae Species 0.000 description 1
- 101710185991 Hepatitis A virus cellular receptor 1 homolog Proteins 0.000 description 1
- 102100031465 Hepatocyte growth factor activator Human genes 0.000 description 1
- 101710184069 Hepatocyte growth factor receptor Proteins 0.000 description 1
- 101710086591 Hepatocyte growth factor-like protein Proteins 0.000 description 1
- 102000004989 Hepsin Human genes 0.000 description 1
- 108090001101 Hepsin Proteins 0.000 description 1
- 102100026119 High affinity immunoglobulin gamma Fc receptor IB Human genes 0.000 description 1
- 101710145893 Histone H2A deubiquitinase MYSM1 Proteins 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000719904 Homo sapiens ADAM DEC1 Proteins 0.000 description 1
- 101001022185 Homo sapiens Alpha-(1,3)-fucosyltransferase 4 Proteins 0.000 description 1
- 101000669649 Homo sapiens Aminopeptidase RNPEPL1 Proteins 0.000 description 1
- 101000889842 Homo sapiens Archaemetzincin-1 Proteins 0.000 description 1
- 101000889833 Homo sapiens Archaemetzincin-2 Proteins 0.000 description 1
- 101000895110 Homo sapiens Ataxin-3-like protein Proteins 0.000 description 1
- 101001111439 Homo sapiens Beta-nerve growth factor Proteins 0.000 description 1
- 101000914211 Homo sapiens CASP8 and FADD-like apoptosis regulator Proteins 0.000 description 1
- 101000793671 Homo sapiens Calpain-6 Proteins 0.000 description 1
- 101000793680 Homo sapiens Calpain-9 Proteins 0.000 description 1
- 101000914326 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 6 Proteins 0.000 description 1
- 101000761509 Homo sapiens Cathepsin K Proteins 0.000 description 1
- 101000983577 Homo sapiens Cathepsin L2 Proteins 0.000 description 1
- 101000910979 Homo sapiens Cathepsin Z Proteins 0.000 description 1
- 101000907961 Homo sapiens Chymotrypsin-like elastase family member 2B Proteins 0.000 description 1
- 101000911952 Homo sapiens Cyclin-dependent kinase 7 Proteins 0.000 description 1
- 101000607486 Homo sapiens Cytochrome b-c1 complex subunit 1, mitochondrial Proteins 0.000 description 1
- 101000746756 Homo sapiens Cytochrome b-c1 complex subunit 2, mitochondrial Proteins 0.000 description 1
- 101000919690 Homo sapiens Cytosolic non-specific dipeptidase Proteins 0.000 description 1
- 101000622317 Homo sapiens Deubiquitinating protein VCPIP1 Proteins 0.000 description 1
- 101000931862 Homo sapiens Dipeptidyl peptidase 3 Proteins 0.000 description 1
- 101000756727 Homo sapiens Disintegrin and metalloproteinase domain-containing protein 23 Proteins 0.000 description 1
- 101000720047 Homo sapiens Disintegrin and metalloproteinase domain-containing protein 32 Proteins 0.000 description 1
- 101100118549 Homo sapiens EGFR gene Proteins 0.000 description 1
- 101000934374 Homo sapiens Early activation antigen CD69 Proteins 0.000 description 1
- 101000898718 Homo sapiens Endoplasmic reticulum aminopeptidase 2 Proteins 0.000 description 1
- 101000978392 Homo sapiens Eotaxin Proteins 0.000 description 1
- 101100066427 Homo sapiens FCGR1A gene Proteins 0.000 description 1
- 101100372760 Homo sapiens FLT1 gene Proteins 0.000 description 1
- 101001023230 Homo sapiens Folate receptor alpha Proteins 0.000 description 1
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 description 1
- 101000746373 Homo sapiens Granulocyte-macrophage colony-stimulating factor Proteins 0.000 description 1
- 101000930801 Homo sapiens HLA class II histocompatibility antigen, DQ alpha 2 chain Proteins 0.000 description 1
- 101001068136 Homo sapiens Hepatitis A virus cellular receptor 1 Proteins 0.000 description 1
- 101000913077 Homo sapiens High affinity immunoglobulin gamma Fc receptor IB Proteins 0.000 description 1
- 101001055308 Homo sapiens Immunoglobulin heavy constant epsilon Proteins 0.000 description 1
- 101000919167 Homo sapiens Inactive carboxypeptidase-like protein X2 Proteins 0.000 description 1
- 101000610630 Homo sapiens Inactive serine protease 35 Proteins 0.000 description 1
- 101000809220 Homo sapiens Inactive ubiquitin carboxyl-terminal hydrolase 50 Proteins 0.000 description 1
- 101000809239 Homo sapiens Inactive ubiquitin carboxyl-terminal hydrolase 53 Proteins 0.000 description 1
- 101000643910 Homo sapiens Inactive ubiquitin carboxyl-terminal hydrolase 54 Proteins 0.000 description 1
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 description 1
- 101000994375 Homo sapiens Integrin alpha-4 Proteins 0.000 description 1
- 101001046683 Homo sapiens Integrin alpha-L Proteins 0.000 description 1
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 1
- 101000599862 Homo sapiens Intercellular adhesion molecule 3 Proteins 0.000 description 1
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 1
- 101001002709 Homo sapiens Interleukin-4 Proteins 0.000 description 1
- 101000599048 Homo sapiens Interleukin-6 receptor subunit alpha Proteins 0.000 description 1
- 101000994432 Homo sapiens Josephin-1 Proteins 0.000 description 1
- 101000994428 Homo sapiens Josephin-2 Proteins 0.000 description 1
- 101001008919 Homo sapiens Kallikrein-10 Proteins 0.000 description 1
- 101000605516 Homo sapiens Kallikrein-12 Proteins 0.000 description 1
- 101000605514 Homo sapiens Kallikrein-13 Proteins 0.000 description 1
- 101000605520 Homo sapiens Kallikrein-14 Proteins 0.000 description 1
- 101000605518 Homo sapiens Kallikrein-15 Proteins 0.000 description 1
- 101000605528 Homo sapiens Kallikrein-2 Proteins 0.000 description 1
- 101001091376 Homo sapiens Kallikrein-4 Proteins 0.000 description 1
- 101001091379 Homo sapiens Kallikrein-5 Proteins 0.000 description 1
- 101001091385 Homo sapiens Kallikrein-6 Proteins 0.000 description 1
- 101001091388 Homo sapiens Kallikrein-7 Proteins 0.000 description 1
- 101001091371 Homo sapiens Kallikrein-8 Proteins 0.000 description 1
- 101001091356 Homo sapiens Kallikrein-9 Proteins 0.000 description 1
- 101000971879 Homo sapiens Kell blood group glycoprotein Proteins 0.000 description 1
- 101000605020 Homo sapiens Large neutral amino acids transporter small subunit 1 Proteins 0.000 description 1
- 101000578830 Homo sapiens Methionine aminopeptidase 1 Proteins 0.000 description 1
- 101000979001 Homo sapiens Methionine aminopeptidase 2 Proteins 0.000 description 1
- 101000946889 Homo sapiens Monocyte differentiation antigen CD14 Proteins 0.000 description 1
- 101000958771 Homo sapiens N-acylethanolamine-hydrolyzing acid amidase Proteins 0.000 description 1
- 101000801664 Homo sapiens Nucleoprotein TPR Proteins 0.000 description 1
- 101000974015 Homo sapiens Nucleosome assembly protein 1-like 1 Proteins 0.000 description 1
- 101000721382 Homo sapiens OTU domain-containing protein 3 Proteins 0.000 description 1
- 101000992283 Homo sapiens Optineurin Proteins 0.000 description 1
- 101000982939 Homo sapiens PAN2-PAN3 deadenylation complex catalytic subunit PAN2 Proteins 0.000 description 1
- 101001126417 Homo sapiens Platelet-derived growth factor receptor alpha Proteins 0.000 description 1
- 101000617725 Homo sapiens Pregnancy-specific beta-1-glycoprotein 2 Proteins 0.000 description 1
- 101000919183 Homo sapiens Probable carboxypeptidase X1 Proteins 0.000 description 1
- 101000605534 Homo sapiens Prostate-specific antigen Proteins 0.000 description 1
- 101000831616 Homo sapiens Protachykinin-1 Proteins 0.000 description 1
- 101001136888 Homo sapiens Proteasome subunit alpha type-3 Proteins 0.000 description 1
- 101000577424 Homo sapiens Proteasome subunit alpha type-4 Proteins 0.000 description 1
- 101001090813 Homo sapiens Proteasome subunit alpha type-6 Proteins 0.000 description 1
- 101000611053 Homo sapiens Proteasome subunit beta type-2 Proteins 0.000 description 1
- 101000735893 Homo sapiens Proteasome subunit beta type-6 Proteins 0.000 description 1
- 101001136954 Homo sapiens Proteasome subunit beta type-7 Proteins 0.000 description 1
- 101000831286 Homo sapiens Protein timeless homolog Proteins 0.000 description 1
- 101000797874 Homo sapiens Putative bifunctional UDP-N-acetylglucosamine transferase and deubiquitinase ALG13 Proteins 0.000 description 1
- 101001116719 Homo sapiens Putative macrophage stimulating 1-like protein Proteins 0.000 description 1
- 101000777204 Homo sapiens Putative ubiquitin carboxyl-terminal hydrolase 41 Proteins 0.000 description 1
- 101000727472 Homo sapiens Reticulon-4 Proteins 0.000 description 1
- 101000752245 Homo sapiens Rho guanine nucleotide exchange factor 5 Proteins 0.000 description 1
- 101000832248 Homo sapiens STAM-binding protein Proteins 0.000 description 1
- 101000684495 Homo sapiens Sentrin-specific protease 1 Proteins 0.000 description 1
- 101000684497 Homo sapiens Sentrin-specific protease 2 Proteins 0.000 description 1
- 101000684503 Homo sapiens Sentrin-specific protease 3 Proteins 0.000 description 1
- 101000684507 Homo sapiens Sentrin-specific protease 5 Proteins 0.000 description 1
- 101000684514 Homo sapiens Sentrin-specific protease 6 Proteins 0.000 description 1
- 101000708013 Homo sapiens Sentrin-specific protease 7 Proteins 0.000 description 1
- 101000708009 Homo sapiens Sentrin-specific protease 8 Proteins 0.000 description 1
- 101000601441 Homo sapiens Serine/threonine-protein kinase Nek2 Proteins 0.000 description 1
- 101000946850 Homo sapiens T-lymphocyte activation antigen CD86 Proteins 0.000 description 1
- 101000637850 Homo sapiens Tolloid-like protein 2 Proteins 0.000 description 1
- 101000835086 Homo sapiens Transferrin receptor protein 2 Proteins 0.000 description 1
- 101000637855 Homo sapiens Transmembrane protease serine 11E Proteins 0.000 description 1
- 101000798715 Homo sapiens Transmembrane protease serine 12 Proteins 0.000 description 1
- 101000798707 Homo sapiens Transmembrane protease serine 13 Proteins 0.000 description 1
- 101000796737 Homo sapiens Tryptase delta Proteins 0.000 description 1
- 101000796738 Homo sapiens Tryptase gamma Proteins 0.000 description 1
- 101000611185 Homo sapiens Tumor necrosis factor receptor superfamily member 5 Proteins 0.000 description 1
- 101000809243 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 10 Proteins 0.000 description 1
- 101000809261 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 11 Proteins 0.000 description 1
- 101000760210 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 12 Proteins 0.000 description 1
- 101000760229 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 13 Proteins 0.000 description 1
- 101000841477 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 14 Proteins 0.000 description 1
- 101000841471 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 15 Proteins 0.000 description 1
- 101000644815 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 16 Proteins 0.000 description 1
- 101000644843 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 19 Proteins 0.000 description 1
- 101000939517 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 2 Proteins 0.000 description 1
- 101000607865 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 20 Proteins 0.000 description 1
- 101000607872 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 21 Proteins 0.000 description 1
- 101000807524 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 22 Proteins 0.000 description 1
- 101000807541 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 24 Proteins 0.000 description 1
- 101000807540 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 25 Proteins 0.000 description 1
- 101000807533 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 26 Proteins 0.000 description 1
- 101000939467 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 28 Proteins 0.000 description 1
- 101000939456 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 29 Proteins 0.000 description 1
- 101000777220 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 3 Proteins 0.000 description 1
- 101000748132 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 30 Proteins 0.000 description 1
- 101000748137 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 31 Proteins 0.000 description 1
- 101000748141 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 32 Proteins 0.000 description 1
- 101000748157 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 33 Proteins 0.000 description 1
- 101000748161 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 34 Proteins 0.000 description 1
- 101000748159 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 35 Proteins 0.000 description 1
- 101000671819 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 36 Proteins 0.000 description 1
- 101000671811 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 37 Proteins 0.000 description 1
- 101000809257 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 4 Proteins 0.000 description 1
- 101000777206 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 40 Proteins 0.000 description 1
- 101000777138 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 42 Proteins 0.000 description 1
- 101000777134 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 43 Proteins 0.000 description 1
- 101000777120 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 44 Proteins 0.000 description 1
- 101000760243 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 45 Proteins 0.000 description 1
- 101000759984 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 46 Proteins 0.000 description 1
- 101000759994 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 47 Proteins 0.000 description 1
- 101000759935 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 49 Proteins 0.000 description 1
- 101000643890 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 5 Proteins 0.000 description 1
- 101000809223 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 51 Proteins 0.000 description 1
- 101000643895 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 6 Proteins 0.000 description 1
- 101000841466 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 8 Proteins 0.000 description 1
- 101001121442 Homo sapiens Ubiquitin thioesterase OTU1 Proteins 0.000 description 1
- 101000644847 Homo sapiens Ubl carboxyl-terminal hydrolase 18 Proteins 0.000 description 1
- 240000005979 Hordeum vulgare Species 0.000 description 1
- 235000007340 Hordeum vulgare Nutrition 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 1
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 1
- 101000926057 Human herpesvirus 2 (strain G) Envelope glycoprotein C Proteins 0.000 description 1
- 101100122503 Human herpesvirus 6A (strain Uganda-1102) gN gene Proteins 0.000 description 1
- 241000711920 Human orthopneumovirus Species 0.000 description 1
- 108010013214 Hyaluronan Receptors Proteins 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- 206010020631 Hypergammaglobulinaemia benign monoclonal Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 108010073807 IgG Receptors Proteins 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 1
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 1
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 1
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 1
- 102100026212 Immunoglobulin heavy constant epsilon Human genes 0.000 description 1
- 102100029326 Inactive carboxypeptidase-like protein X2 Human genes 0.000 description 1
- 102100040339 Inactive serine protease 35 Human genes 0.000 description 1
- 102100031071 Inactive serine protease 54 Human genes 0.000 description 1
- 101710171806 Inactive serine protease 54 Proteins 0.000 description 1
- 102100038414 Inactive ubiquitin carboxyl-terminal hydrolase 50 Human genes 0.000 description 1
- 102100038425 Inactive ubiquitin carboxyl-terminal hydrolase 53 Human genes 0.000 description 1
- 102100021014 Inactive ubiquitin carboxyl-terminal hydrolase 54 Human genes 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241001500351 Influenzavirus A Species 0.000 description 1
- 241001500350 Influenzavirus B Species 0.000 description 1
- 102100025087 Insulin receptor substrate 1 Human genes 0.000 description 1
- 101710201824 Insulin receptor substrate 1 Proteins 0.000 description 1
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 1
- 101710184277 Insulin-like growth factor 1 receptor Proteins 0.000 description 1
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 1
- 101710123016 Integrin alpha-L Proteins 0.000 description 1
- 102100022337 Integrin alpha-V Human genes 0.000 description 1
- 108010041012 Integrin alpha4 Proteins 0.000 description 1
- 108010041014 Integrin alpha5 Proteins 0.000 description 1
- 108010047852 Integrin alphaVbeta3 Proteins 0.000 description 1
- 108050004144 Integrin beta-1 subunit Proteins 0.000 description 1
- 102000017341 Integrin beta-2 subunit Human genes 0.000 description 1
- 108010060632 Interleukin-2 Receptor beta Subunit Proteins 0.000 description 1
- 102000008193 Interleukin-2 Receptor beta Subunit Human genes 0.000 description 1
- 101710184892 Intermediate cleaving peptidase 55 Proteins 0.000 description 1
- 102100032732 Josephin-1 Human genes 0.000 description 1
- 102100032731 Josephin-2 Human genes 0.000 description 1
- 101710176219 Kallikrein-1 Proteins 0.000 description 1
- 102100027613 Kallikrein-10 Human genes 0.000 description 1
- 102100038318 Kallikrein-12 Human genes 0.000 description 1
- 102100038315 Kallikrein-13 Human genes 0.000 description 1
- 102100038298 Kallikrein-14 Human genes 0.000 description 1
- 102100038301 Kallikrein-15 Human genes 0.000 description 1
- 102100038356 Kallikrein-2 Human genes 0.000 description 1
- 102100034872 Kallikrein-4 Human genes 0.000 description 1
- 102100034868 Kallikrein-5 Human genes 0.000 description 1
- 102100034866 Kallikrein-6 Human genes 0.000 description 1
- 102100034867 Kallikrein-7 Human genes 0.000 description 1
- 102100034870 Kallikrein-8 Human genes 0.000 description 1
- 102100034876 Kallikrein-9 Human genes 0.000 description 1
- 102100021447 Kell blood group glycoprotein Human genes 0.000 description 1
- 102000011782 Keratins Human genes 0.000 description 1
- 108010076876 Keratins Proteins 0.000 description 1
- 108010092694 L-Selectin Proteins 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- 241001235216 Larix decidua Species 0.000 description 1
- 101710097665 Leucine aminopeptidase 1 Proteins 0.000 description 1
- 108010004098 Leucyl aminopeptidase Proteins 0.000 description 1
- 102000002704 Leucyl aminopeptidase Human genes 0.000 description 1
- 102100022118 Leukotriene A-4 hydrolase Human genes 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 102000004317 Lyases Human genes 0.000 description 1
- 108090000856 Lyases Proteins 0.000 description 1
- 108010064548 Lymphocyte Function-Associated Antigen-1 Proteins 0.000 description 1
- 108090000542 Lymphotoxin-alpha Proteins 0.000 description 1
- 108090000362 Lymphotoxin-beta Proteins 0.000 description 1
- 108010085169 Lysine carboxypeptidase Proteins 0.000 description 1
- 108091007144 MMP23A Proteins 0.000 description 1
- 102000008904 MPN domains Human genes 0.000 description 1
- 108050000834 MPN domains Proteins 0.000 description 1
- 108010000410 MSH receptor Proteins 0.000 description 1
- 108030001712 Macrophage elastases Proteins 0.000 description 1
- 101000962498 Macropis fulvipes Macropin Proteins 0.000 description 1
- 101710125418 Major capsid protein Proteins 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- 101710119290 Mast cell carboxypeptidase A Proteins 0.000 description 1
- 101710101685 Matrix metallopeptidase-21 Proteins 0.000 description 1
- 102100029693 Matrix metalloproteinase-20 Human genes 0.000 description 1
- 102100029692 Matrix metalloproteinase-21 Human genes 0.000 description 1
- 201000005505 Measles Diseases 0.000 description 1
- 108010047230 Member 1 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 1
- 108050004622 Membrane metallo-endopeptidase-like 1 Proteins 0.000 description 1
- 102100024197 Membrane metallo-endopeptidase-like 1 Human genes 0.000 description 1
- NPPQSCRMBWNHMW-UHFFFAOYSA-N Meprobamate Chemical compound NC(=O)OCC(C)(CCC)COC(N)=O NPPQSCRMBWNHMW-UHFFFAOYSA-N 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 102100028379 Methionine aminopeptidase 1 Human genes 0.000 description 1
- 102100023174 Methionine aminopeptidase 2 Human genes 0.000 description 1
- 102100025321 Mitochondrial-processing peptidase subunit alpha Human genes 0.000 description 1
- 101710145147 Mitochondrial-processing peptidase subunit alpha Proteins 0.000 description 1
- 102100035877 Monocyte differentiation antigen CD14 Human genes 0.000 description 1
- 241000713333 Mouse mammary tumor virus Species 0.000 description 1
- 101000686985 Mouse mammary tumor virus (strain C3H) Protein PR73 Proteins 0.000 description 1
- 101710164418 Movement protein TGB2 Proteins 0.000 description 1
- 108010034536 Mucin 5AC Proteins 0.000 description 1
- 102000009616 Mucin 5AC Human genes 0.000 description 1
- 102100038732 Mucosa-associated lymphoid tissue lymphoma translocation protein 1 Human genes 0.000 description 1
- 241000711386 Mumps virus Species 0.000 description 1
- 101000844719 Mus musculus Deleted in malignant brain tumors 1 protein Proteins 0.000 description 1
- 101100335081 Mus musculus Flt3 gene Proteins 0.000 description 1
- 101000605519 Mus musculus Kallikrein-14 Proteins 0.000 description 1
- 101100400378 Mus musculus Marveld2 gene Proteins 0.000 description 1
- 101100465339 Mus musculus Prss39 gene Proteins 0.000 description 1
- 101000610625 Mus musculus Serine protease 33 Proteins 0.000 description 1
- 101000934342 Mus musculus T-cell surface glycoprotein CD5 Proteins 0.000 description 1
- 101100046559 Mus musculus Tnfrsf12a gene Proteins 0.000 description 1
- 101000638178 Mus musculus Transmembrane protease serine 2 Proteins 0.000 description 1
- 101000807563 Mus musculus Ufm1-specific protease 1 Proteins 0.000 description 1
- 101100107287 Mus musculus Zranb1 gene Proteins 0.000 description 1
- 102100034681 Myeloblastin Human genes 0.000 description 1
- 108090000973 Myeloblastin Proteins 0.000 description 1
- 208000014767 Myeloproliferative disease Diseases 0.000 description 1
- 101001055320 Myxine glutinosa Insulin-like growth factor Proteins 0.000 description 1
- 102100031895 N-acetylated-alpha-linked acidic dipeptidase 2 Human genes 0.000 description 1
- 101710093461 N-acetylated-alpha-linked acidic dipeptidase 2 Proteins 0.000 description 1
- 102100038360 N-acylethanolamine-hydrolyzing acid amidase Human genes 0.000 description 1
- CQOVPNPJLQNMDC-UHFFFAOYSA-N N-beta-alanyl-L-histidine Natural products NCCC(=O)NC(C(O)=O)CC1=CN=CN1 CQOVPNPJLQNMDC-UHFFFAOYSA-N 0.000 description 1
- 102100035486 Nectin-4 Human genes 0.000 description 1
- 101710043865 Nectin-4 Proteins 0.000 description 1
- 102000048850 Neoplasm Genes Human genes 0.000 description 1
- 108700019961 Neoplasm Genes Proteins 0.000 description 1
- 108010069196 Neural Cell Adhesion Molecules Proteins 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 108090000812 Neurolysin Proteins 0.000 description 1
- 102100023072 Neurolysin, mitochondrial Human genes 0.000 description 1
- 102000004207 Neuropilin-1 Human genes 0.000 description 1
- 101100342977 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) leu-1 gene Proteins 0.000 description 1
- 102100035484 Neurotrypsin Human genes 0.000 description 1
- 102100037228 Nicalin Human genes 0.000 description 1
- 101710134626 Nicalin Proteins 0.000 description 1
- 102100033615 Nucleoprotein TPR Human genes 0.000 description 1
- 102100025196 OTU domain-containing protein 3 Human genes 0.000 description 1
- 102100025194 OTU domain-containing protein 5 Human genes 0.000 description 1
- 101710089460 OTU domain-containing protein 5 Proteins 0.000 description 1
- 101710090551 OTU domain-containing protein 5-A Proteins 0.000 description 1
- 108010042215 OX40 Ligand Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 102100026306 Ovochymase-2 Human genes 0.000 description 1
- 101710205346 Ovochymase-2 Proteins 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 108010035766 P-Selectin Proteins 0.000 description 1
- 102100027016 PAN2-PAN3 deadenylation complex catalytic subunit PAN2 Human genes 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 108030001694 Pappalysin-1 Proteins 0.000 description 1
- 102000037728 Pappalysin-1 Human genes 0.000 description 1
- 102000033039 Pappalysin-2 Human genes 0.000 description 1
- 108091009503 Pappalysin-2 Proteins 0.000 description 1
- 101710120145 Paracaspase Proteins 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 102100027006 Paraplegin Human genes 0.000 description 1
- 101710083869 Paraplegin Proteins 0.000 description 1
- 208000002774 Paraproteinemias Diseases 0.000 description 1
- 108010067902 Peptide Library Proteins 0.000 description 1
- 108010001441 Phosphopeptides Proteins 0.000 description 1
- 101710201137 Photosystem II manganese-stabilizing polypeptide Proteins 0.000 description 1
- 102000003827 Plasma Kallikrein Human genes 0.000 description 1
- 108090000113 Plasma Kallikrein Proteins 0.000 description 1
- 108010022425 Platelet Glycoprotein GPIIb-IIIa Complex Proteins 0.000 description 1
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 1
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 1
- 108010068588 Platelet-Derived Growth Factor alpha Receptor Proteins 0.000 description 1
- 208000002151 Pleural effusion Diseases 0.000 description 1
- 241000276498 Pollachius virens Species 0.000 description 1
- 229920000805 Polyaspartic acid Polymers 0.000 description 1
- 229920002873 Polyethylenimine Polymers 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- 102100022033 Presenilin-1 Human genes 0.000 description 1
- 108010036933 Presenilin-1 Proteins 0.000 description 1
- 102000012419 Presenilin-2 Human genes 0.000 description 1
- 108010036908 Presenilin-2 Proteins 0.000 description 1
- 101710151424 Probable Ufm1-specific protease 2 Proteins 0.000 description 1
- 102100029401 Probable carboxypeptidase X1 Human genes 0.000 description 1
- 101710082688 Probable leucine aminopeptidase 1 Proteins 0.000 description 1
- 102100029500 Prostasin Human genes 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 102100024304 Protachykinin-1 Human genes 0.000 description 1
- 102100035908 Proteasome subunit alpha type-3 Human genes 0.000 description 1
- 102100028813 Proteasome subunit alpha type-4 Human genes 0.000 description 1
- 102100034664 Proteasome subunit alpha type-6 Human genes 0.000 description 1
- 102000017850 Proteasome subunit alpha2 Human genes 0.000 description 1
- 108050007073 Proteasome subunit alpha2 Proteins 0.000 description 1
- 102000001593 Proteasome subunit alpha5 Human genes 0.000 description 1
- 108050009823 Proteasome subunit alpha5 Proteins 0.000 description 1
- 102000017863 Proteasome subunit alpha6 Human genes 0.000 description 1
- 108050007094 Proteasome subunit alpha6 Proteins 0.000 description 1
- 102100040400 Proteasome subunit beta type-2 Human genes 0.000 description 1
- 102100033755 Proteasome subunit beta type-3 Human genes 0.000 description 1
- 101710094500 Proteasome subunit beta type-3 Proteins 0.000 description 1
- 102100036128 Proteasome subunit beta type-6 Human genes 0.000 description 1
- 102100035763 Proteasome subunit beta type-7 Human genes 0.000 description 1
- 101800001072 Protein 1A Proteins 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 description 1
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 description 1
- 101800000442 Protein X2 Proteins 0.000 description 1
- 102220603706 Protein jagunal homolog 1_M24A_mutation Human genes 0.000 description 1
- 102000016611 Proteoglycans Human genes 0.000 description 1
- 108010067787 Proteoglycans Proteins 0.000 description 1
- 108010089836 Proto-Oncogene Proteins c-met Proteins 0.000 description 1
- 102000008022 Proto-Oncogene Proteins c-met Human genes 0.000 description 1
- 102100033192 Puromycin-sensitive aminopeptidase Human genes 0.000 description 1
- 102100032337 Putative bifunctional UDP-N-acetylglucosamine transferase and deubiquitinase ALG13 Human genes 0.000 description 1
- 102100024820 Putative macrophage stimulating 1-like protein Human genes 0.000 description 1
- 102100031285 Putative ubiquitin carboxyl-terminal hydrolase 41 Human genes 0.000 description 1
- 108090000919 Pyroglutamyl-Peptidase I Proteins 0.000 description 1
- 102100031108 Pyroglutamyl-peptidase 1 Human genes 0.000 description 1
- 102000004892 Pyroglutamyl-peptidase II Human genes 0.000 description 1
- 108090001002 Pyroglutamyl-peptidase II Proteins 0.000 description 1
- 101710100968 Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 108090000783 Renin Proteins 0.000 description 1
- 102100028255 Renin Human genes 0.000 description 1
- 101710122685 Reticulon-4 Proteins 0.000 description 1
- 102100033717 Retroviral-like aspartic protease 1 Human genes 0.000 description 1
- 101710184461 Retroviral-like aspartic protease 1 Proteins 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 101710083287 SLAM family member 7 Proteins 0.000 description 1
- 108091006207 SLC-Transporter Proteins 0.000 description 1
- 102000037054 SLC-Transporter Human genes 0.000 description 1
- 108091006313 SLC3A2 Proteins 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 101100123851 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) HER1 gene Proteins 0.000 description 1
- 241000239226 Scorpiones Species 0.000 description 1
- 102100031312 Secernin-1 Human genes 0.000 description 1
- 101710186590 Secernin-1 Proteins 0.000 description 1
- 102100031318 Secernin-2 Human genes 0.000 description 1
- 101710186589 Secernin-2 Proteins 0.000 description 1
- 102100031320 Secernin-3 Human genes 0.000 description 1
- 101710186591 Secernin-3 Proteins 0.000 description 1
- 102100030053 Secreted frizzled-related protein 3 Human genes 0.000 description 1
- 201000010208 Seminoma Diseases 0.000 description 1
- 108010031091 Separase Proteins 0.000 description 1
- 102000005734 Separase Human genes 0.000 description 1
- 102100021225 Serine hydroxymethyltransferase, cytosolic Human genes 0.000 description 1
- 102100040107 Serine protease 27 Human genes 0.000 description 1
- 101710197422 Serine protease 27 Proteins 0.000 description 1
- 102100038769 Serine protease 38 Human genes 0.000 description 1
- 101710197460 Serine protease 38 Proteins 0.000 description 1
- 102100037703 Serine/threonine-protein kinase Nek2 Human genes 0.000 description 1
- 101000873420 Simian virus 40 SV40 early leader protein Proteins 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 102000013275 Somatomedins Human genes 0.000 description 1
- 101000668858 Spinacia oleracea 30S ribosomal protein S1, chloroplastic Proteins 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 241000191963 Staphylococcus epidermidis Species 0.000 description 1
- 206010042135 Stomatitis necrotising Diseases 0.000 description 1
- 101000898746 Streptomyces clavuligerus Clavaminate synthase 1 Proteins 0.000 description 1
- 101800001271 Surface protein Proteins 0.000 description 1
- 108090000058 Syndecan-1 Proteins 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 230000024932 T cell mediated immunity Effects 0.000 description 1
- 101710165202 T-cell surface antigen CD2 Proteins 0.000 description 1
- 102100034924 T-lymphocyte activation antigen CD86 Human genes 0.000 description 1
- 102000006467 TATA-Box Binding Protein Human genes 0.000 description 1
- 108010044281 TATA-Box Binding Protein Proteins 0.000 description 1
- 108010014401 TWEAK Receptor Proteins 0.000 description 1
- 102000016946 TWEAK Receptor Human genes 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 102000013980 Testisin Human genes 0.000 description 1
- 108050003829 Testisin Proteins 0.000 description 1
- 206010043376 Tetanus Diseases 0.000 description 1
- 108010055044 Tetanus Toxin Proteins 0.000 description 1
- 102100031293 Thimet oligopeptidase Human genes 0.000 description 1
- 102000002938 Thrombospondin Human genes 0.000 description 1
- 108060008245 Thrombospondin Proteins 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 102000057032 Tissue Kallikreins Human genes 0.000 description 1
- 102100031996 Tolloid-like protein 1 Human genes 0.000 description 1
- 102100031997 Tolloid-like protein 2 Human genes 0.000 description 1
- 102100026144 Transferrin receptor protein 1 Human genes 0.000 description 1
- 102100026143 Transferrin receptor protein 2 Human genes 0.000 description 1
- 102000006747 Transforming Growth Factor alpha Human genes 0.000 description 1
- 102000046299 Transforming Growth Factor beta1 Human genes 0.000 description 1
- 108010009583 Transforming Growth Factors Proteins 0.000 description 1
- 102000009618 Transforming Growth Factors Human genes 0.000 description 1
- 101800004564 Transforming growth factor alpha Proteins 0.000 description 1
- 101800002279 Transforming growth factor beta-1 Proteins 0.000 description 1
- 102100032469 Transmembrane protease serine 12 Human genes 0.000 description 1
- 102100032472 Transmembrane protease serine 5 Human genes 0.000 description 1
- 101710081833 Transmembrane protease serine 5 Proteins 0.000 description 1
- 102100032453 Transmembrane protease serine 7 Human genes 0.000 description 1
- 101710081837 Transmembrane protease serine 7 Proteins 0.000 description 1
- 101710190034 Trophoblast glycoprotein Proteins 0.000 description 1
- 102100034392 Trypsin-2 Human genes 0.000 description 1
- 101710119666 Trypsin-2 Proteins 0.000 description 1
- 102100032760 Tryptase delta Human genes 0.000 description 1
- 102100032761 Tryptase gamma Human genes 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 102100033470 Tubulointerstitial nephritis antigen Human genes 0.000 description 1
- 101710185398 Tubulointerstitial nephritis antigen Proteins 0.000 description 1
- 102100033469 Tubulointerstitial nephritis antigen-like Human genes 0.000 description 1
- 101710159742 Tubulointerstitial nephritis antigen-like Proteins 0.000 description 1
- 108010047933 Tumor Necrosis Factor alpha-Induced Protein 3 Proteins 0.000 description 1
- 102100024596 Tumor necrosis factor alpha-induced protein 3 Human genes 0.000 description 1
- 101710097161 Tumor necrosis factor ligand superfamily member 11 Proteins 0.000 description 1
- 101710181056 Tumor necrosis factor ligand superfamily member 13B Proteins 0.000 description 1
- 101710178416 Tumor necrosis factor receptor superfamily member 12A Proteins 0.000 description 1
- 206010054094 Tumour necrosis Diseases 0.000 description 1
- 208000035896 Twin-reversed arterial perfusion sequence Diseases 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 101150004957 UL25 gene Proteins 0.000 description 1
- 101150081727 UL32 gene Proteins 0.000 description 1
- 101150004685 UL48 gene Proteins 0.000 description 1
- 101150081415 UL55 gene Proteins 0.000 description 1
- 101150022492 UL83 gene Proteins 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- 102000044159 Ubiquitin Human genes 0.000 description 1
- 102100038426 Ubiquitin carboxyl-terminal hydrolase 10 Human genes 0.000 description 1
- 102100038462 Ubiquitin carboxyl-terminal hydrolase 11 Human genes 0.000 description 1
- 102100024662 Ubiquitin carboxyl-terminal hydrolase 12 Human genes 0.000 description 1
- 102100024720 Ubiquitin carboxyl-terminal hydrolase 13 Human genes 0.000 description 1
- 102100029163 Ubiquitin carboxyl-terminal hydrolase 14 Human genes 0.000 description 1
- 102100029164 Ubiquitin carboxyl-terminal hydrolase 15 Human genes 0.000 description 1
- 102100020730 Ubiquitin carboxyl-terminal hydrolase 16 Human genes 0.000 description 1
- 102100020728 Ubiquitin carboxyl-terminal hydrolase 19 Human genes 0.000 description 1
- 102100029643 Ubiquitin carboxyl-terminal hydrolase 2 Human genes 0.000 description 1
- 102100039920 Ubiquitin carboxyl-terminal hydrolase 20 Human genes 0.000 description 1
- 102100039918 Ubiquitin carboxyl-terminal hydrolase 21 Human genes 0.000 description 1
- 102100037184 Ubiquitin carboxyl-terminal hydrolase 22 Human genes 0.000 description 1
- 102100037176 Ubiquitin carboxyl-terminal hydrolase 24 Human genes 0.000 description 1
- 102100037179 Ubiquitin carboxyl-terminal hydrolase 25 Human genes 0.000 description 1
- 102100037180 Ubiquitin carboxyl-terminal hydrolase 26 Human genes 0.000 description 1
- 102100029821 Ubiquitin carboxyl-terminal hydrolase 28 Human genes 0.000 description 1
- 102100029818 Ubiquitin carboxyl-terminal hydrolase 29 Human genes 0.000 description 1
- 102100031287 Ubiquitin carboxyl-terminal hydrolase 3 Human genes 0.000 description 1
- 102100040052 Ubiquitin carboxyl-terminal hydrolase 30 Human genes 0.000 description 1
- 102100040049 Ubiquitin carboxyl-terminal hydrolase 31 Human genes 0.000 description 1
- 102100040050 Ubiquitin carboxyl-terminal hydrolase 32 Human genes 0.000 description 1
- 102100040047 Ubiquitin carboxyl-terminal hydrolase 33 Human genes 0.000 description 1
- 102100040096 Ubiquitin carboxyl-terminal hydrolase 34 Human genes 0.000 description 1
- 102100040048 Ubiquitin carboxyl-terminal hydrolase 35 Human genes 0.000 description 1
- 102100040109 Ubiquitin carboxyl-terminal hydrolase 36 Human genes 0.000 description 1
- 102100040111 Ubiquitin carboxyl-terminal hydrolase 37 Human genes 0.000 description 1
- 102100038463 Ubiquitin carboxyl-terminal hydrolase 4 Human genes 0.000 description 1
- 102100031284 Ubiquitin carboxyl-terminal hydrolase 40 Human genes 0.000 description 1
- 102100031310 Ubiquitin carboxyl-terminal hydrolase 42 Human genes 0.000 description 1
- 102100031311 Ubiquitin carboxyl-terminal hydrolase 43 Human genes 0.000 description 1
- 102100031306 Ubiquitin carboxyl-terminal hydrolase 44 Human genes 0.000 description 1
- 102100024718 Ubiquitin carboxyl-terminal hydrolase 45 Human genes 0.000 description 1
- 102100025025 Ubiquitin carboxyl-terminal hydrolase 46 Human genes 0.000 description 1
- 102100025029 Ubiquitin carboxyl-terminal hydrolase 47 Human genes 0.000 description 1
- 102100025044 Ubiquitin carboxyl-terminal hydrolase 49 Human genes 0.000 description 1
- 102100021017 Ubiquitin carboxyl-terminal hydrolase 5 Human genes 0.000 description 1
- 102100038433 Ubiquitin carboxyl-terminal hydrolase 51 Human genes 0.000 description 1
- 102100021015 Ubiquitin carboxyl-terminal hydrolase 6 Human genes 0.000 description 1
- 102100021013 Ubiquitin carboxyl-terminal hydrolase 7 Human genes 0.000 description 1
- 102100029088 Ubiquitin carboxyl-terminal hydrolase 8 Human genes 0.000 description 1
- 102000001591 Ubiquitin specific peptidase 1 Human genes 0.000 description 1
- 108050009822 Ubiquitin specific peptidase 1 Proteins 0.000 description 1
- 102100040461 Ubiquitin thioesterase OTUB1 Human genes 0.000 description 1
- 108050001601 Ubiquitin thioesterase OTUB1 Proteins 0.000 description 1
- 102100025914 Ubiquitin thioesterase OTUB2 Human genes 0.000 description 1
- 108050001615 Ubiquitin thioesterase OTUB2 Proteins 0.000 description 1
- 108700011958 Ubiquitin-Specific Peptidase 7 Proteins 0.000 description 1
- 102000001522 Ubiquitin-specific peptidase 38 Human genes 0.000 description 1
- 108050009759 Ubiquitin-specific peptidase 38 Proteins 0.000 description 1
- 102000001537 Ubiquitin-specific peptidase 48 Human genes 0.000 description 1
- 108050009775 Ubiquitin-specific peptidase 48 Proteins 0.000 description 1
- 102100020726 Ubl carboxyl-terminal hydrolase 18 Human genes 0.000 description 1
- 101710155450 Ufm1-specific protease 2 Proteins 0.000 description 1
- 102100039937 Ufm1-specific protease 2 Human genes 0.000 description 1
- 102100039037 Vascular endothelial growth factor A Human genes 0.000 description 1
- 108010048673 Vitronectin Receptors Proteins 0.000 description 1
- 108010020277 WD repeat containing planar cell polarity effector Proteins 0.000 description 1
- 102100038359 Xaa-Pro aminopeptidase 3 Human genes 0.000 description 1
- 102100039662 Xaa-Pro dipeptidase Human genes 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 108010023079 activin B Proteins 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000033289 adaptive immune response Effects 0.000 description 1
- 210000004404 adrenal cortex Anatomy 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 239000013566 allergen Substances 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- HBBOZFUQJDYASD-LPHOMBEVSA-N alpha-L-Fucp-(1->3)-[beta-D-Galp-(1->4)]-beta-D-GlcpNAc Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](O[C@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)[C@@H](CO)O[C@@H](O)[C@@H]1NC(C)=O HBBOZFUQJDYASD-LPHOMBEVSA-N 0.000 description 1
- CMQZRJBJDCVIEY-JEOLMMCMSA-N alpha-L-Fucp-(1->3)-[beta-D-Galp-(1->4)]-beta-D-GlcpNAc-(1->3)-beta-D-Galp-(1->4)-D-Glcp Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](O[C@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)[C@@H](CO)O[C@@H](O[C@@H]2[C@H]([C@H](O[C@@H]3[C@H](OC(O)[C@H](O)[C@H]3O)CO)O[C@H](CO)[C@@H]2O)O)[C@@H]1NC(C)=O CMQZRJBJDCVIEY-JEOLMMCMSA-N 0.000 description 1
- 108010003977 aminoacylase I Proteins 0.000 description 1
- 229960002684 aminocaproic acid Drugs 0.000 description 1
- 108090000449 aminopeptidase B Proteins 0.000 description 1
- 108010064539 amyloid beta-protein (1-42) Proteins 0.000 description 1
- 206010002022 amyloidosis Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003527 anti-angiogenesis Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000002494 anti-cea effect Effects 0.000 description 1
- 230000003409 anti-rejection Effects 0.000 description 1
- 230000005809 anti-tumor immunity Effects 0.000 description 1
- 229940124691 antibody therapeutics Drugs 0.000 description 1
- 230000007416 antiviral immune response Effects 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 210000001130 astrocyte Anatomy 0.000 description 1
- 230000003305 autocrine Effects 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 108010089934 carbohydrase Proteins 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 229940044199 carnosine Drugs 0.000 description 1
- CQOVPNPJLQNMDC-ZETCQYMHSA-N carnosine Chemical compound [NH3+]CCC(=O)N[C@H](C([O-])=O)CC1=CNC=N1 CQOVPNPJLQNMDC-ZETCQYMHSA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 150000001783 ceramides Chemical class 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 108010039524 chondroitin sulfate proteoglycan 4 Proteins 0.000 description 1
- 208000024207 chronic leukemia Diseases 0.000 description 1
- 108010057788 chymotrypsin B Proteins 0.000 description 1
- 229940126051 coagulation factor XIa Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 108010022822 collapsin response mediator protein-2 Proteins 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000001351 cycling effect Effects 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 210000005220 cytoplasmic tail Anatomy 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 230000005860 defense response to virus Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- CEJLBZWIKQJOAT-UHFFFAOYSA-N dichloroisocyanuric acid Chemical compound ClN1C(=O)NC(=O)N(Cl)C1=O CEJLBZWIKQJOAT-UHFFFAOYSA-N 0.000 description 1
- FOCAHLGSDWHSAH-UHFFFAOYSA-N difluoromethanethione Chemical compound FC(F)=S FOCAHLGSDWHSAH-UHFFFAOYSA-N 0.000 description 1
- 108091022884 dihydropyrimidinase Proteins 0.000 description 1
- 229960001174 ecallantide Drugs 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000000763 evoking effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 108091005640 farnesylated proteins Proteins 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- 102000006815 folate receptor Human genes 0.000 description 1
- 108020005243 folate receptor Proteins 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 244000053095 fungal pathogen Species 0.000 description 1
- 101150055782 gH gene Proteins 0.000 description 1
- 210000004475 gamma-delta t lymphocyte Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229960000578 gemtuzumab Drugs 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 description 1
- 108010051667 glutamyl-glutamyl-asparagyl-leucyl-leucyl-aspartyl-phenylalanyl-valyl-arginyl-phenylalanine Proteins 0.000 description 1
- 229930004094 glycosylphosphatidylinositol Natural products 0.000 description 1
- 235000019410 glycyrrhizin Nutrition 0.000 description 1
- 239000002622 gonadotropin Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000005252 hepatitis A Diseases 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 238000002657 hormone replacement therapy Methods 0.000 description 1
- 102000044095 human FCGR1A Human genes 0.000 description 1
- 102000055229 human IL4 Human genes 0.000 description 1
- 102000058223 human VEGFA Human genes 0.000 description 1
- 235000020256 human milk Nutrition 0.000 description 1
- 210000004251 human milk Anatomy 0.000 description 1
- 229940099552 hyaluronan Drugs 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- KIUKXJAPPMFGSW-MNSSHETKSA-N hyaluronan Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H](C(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-MNSSHETKSA-N 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 229940027941 immunoglobulin g Drugs 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000011293 immunotherapeutic strategy Methods 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000000126 in silico method Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 108010067479 inhibin B Proteins 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 108010043603 integrin alpha4beta7 Proteins 0.000 description 1
- 108010042442 integrin alphaEbeta7 Proteins 0.000 description 1
- 108040006858 interleukin-6 receptor activity proteins Proteins 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- PGLTVOMIXTUURA-UHFFFAOYSA-N iodoacetamide Chemical compound NC(=O)CI PGLTVOMIXTUURA-UHFFFAOYSA-N 0.000 description 1
- JDNTWHVOXJZDSN-UHFFFAOYSA-N iodoacetic acid Chemical compound OC(=O)CI JDNTWHVOXJZDSN-UHFFFAOYSA-N 0.000 description 1
- 229960005386 ipilimumab Drugs 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 108010076401 isopeptidase Proteins 0.000 description 1
- 229940018902 kalbitor Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 108010072713 leukotriene A4 hydrolase Proteins 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 108091007168 mammalian tolloid-like Proteins 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 108091007169 meprins Proteins 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 238000002493 microarray Methods 0.000 description 1
- 210000000274 microglia Anatomy 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000001483 mobilizing effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 201000005328 monoclonal gammopathy of uncertain significance Diseases 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 210000000865 mononuclear phagocyte system Anatomy 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 108010037733 neurotrypsin Proteins 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000002815 nickel Chemical group 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 201000008585 noma Diseases 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 101710135378 pH 6 antigen Proteins 0.000 description 1
- 201000010279 papillary renal cell carcinoma Diseases 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000000849 parathyroid Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229940066716 pepsin a Drugs 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 210000001986 peyer's patch Anatomy 0.000 description 1
- 210000000680 phagosome Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000003114 pinocytic effect Effects 0.000 description 1
- 108010025221 plasma protein Z Proteins 0.000 description 1
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 1
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 description 1
- 108010064470 polyaspartate Proteins 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 108010066823 proline dipeptidase Proteins 0.000 description 1
- 108010031970 prostasin Proteins 0.000 description 1
- 201000005825 prostate adenocarcinoma Diseases 0.000 description 1
- 238000000575 proteomic method Methods 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 210000003289 regulatory T cell Anatomy 0.000 description 1
- 231100000205 reproductive and developmental toxicity Toxicity 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 201000005404 rubella Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 150000003408 sphingolipids Chemical class 0.000 description 1
- 238000011476 stem cell transplantation Methods 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- ADNPLDHMAVUMIW-CUZNLEPHSA-N substance P Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 description 1
- 231100000617 superantigen Toxicity 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 101150047061 tag-72 gene Proteins 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940118376 tetanus toxin Drugs 0.000 description 1
- 229960000814 tetanus toxoid Drugs 0.000 description 1
- 229940126622 therapeutic monoclonal antibody Drugs 0.000 description 1
- 108010073106 thimet oligopeptidase Proteins 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229940099456 transforming growth factor beta 1 Drugs 0.000 description 1
- 230000001810 trypsinlike Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 108010014402 tyrosinase-related protein-1 Proteins 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 230000036325 urinary excretion Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- WHNFPRLDDSXQCL-UAZQEYIDSA-N α-msh Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(N)=O)NC(=O)[C@H](CO)NC(C)=O)C1=CC=C(O)C=C1 WHNFPRLDDSXQCL-UAZQEYIDSA-N 0.000 description 1
- ORQXBVXKBGUSBA-QMMMGPOBSA-N β-cyclohexyl-alanine Chemical group OC(=O)[C@@H](N)CC1CCCCC1 ORQXBVXKBGUSBA-QMMMGPOBSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
-
- A61K47/48715—
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
- A61K38/2013—IL-2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
- A61K38/2026—IL-4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
- A61K38/204—IL-6
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/08—Clostridium, e.g. Clostridium tetani
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A61K39/145—Orthomyxoviridae, e.g. influenza virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A61K39/235—Adenoviridae
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A61K39/245—Herpetoviridae, e.g. herpes simplex virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A61K47/48276—
-
- A61K47/4833—
-
- A61K47/48415—
-
- A61K47/48584—
-
- A61K47/4863—
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
- A61K47/646—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the entire peptide or protein drug conjugate elicits an immune response, e.g. conjugate vaccines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
- A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
- A61K47/6867—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from a cell of a blood cancer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/58—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation
- A61K2039/585—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation wherein the target is cancer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
- A61K2039/6031—Proteins
- A61K2039/6056—Antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/62—Medicinal preparations containing antigens or antibodies characterised by the link between antigen and carrier
- A61K2039/627—Medicinal preparations containing antigens or antibodies characterised by the link between antigen and carrier characterised by the linker
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
- A61K47/6853—Carcino-embryonic antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
- A61K47/6857—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from lung cancer cell
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
- A61K47/6859—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from liver or pancreas cancer cell
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
- A61K47/6861—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from kidney or bladder cancer cell
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
- A61K47/6863—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from stomach or intestines cancer cell
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
- A61K47/6865—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from skin, nerves or brain cancer cell
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
- A61K47/6869—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from a cell of the reproductive system: ovaria, uterus, testes, prostate
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
- C07K14/01—DNA viruses
- C07K14/03—Herpetoviridae, e.g. pseudorabies virus
- C07K14/04—Varicella-zoster virus
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
- C07K14/01—DNA viruses
- C07K14/03—Herpetoviridae, e.g. pseudorabies virus
- C07K14/04—Varicella-zoster virus
- C07K14/045—Cytomegalovirus
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
- C07K14/01—DNA viruses
- C07K14/03—Herpetoviridae, e.g. pseudorabies virus
- C07K14/05—Epstein-Barr virus
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
- C07K14/08—RNA viruses
- C07K14/085—Picornaviridae, e.g. coxsackie virus, echovirus, enterovirus
- C07K14/095—Rhinovirus
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
- C07K14/08—RNA viruses
- C07K14/11—Orthomyxoviridae, e.g. influenza virus
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
- C07K14/08—RNA viruses
- C07K14/115—Paramyxoviridae, e.g. parainfluenza virus
- C07K14/12—Mumps virus; Measles virus
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/70539—MHC-molecules, e.g. HLA-molecules
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2806—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2875—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
- C07K16/3007—Carcino-embryonic Antigens
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
- C07K16/3015—Breast
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
- C07K16/3023—Lung
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
- C07K16/3038—Kidney, bladder
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
- C07K16/3046—Stomach, Intestines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
- C07K16/3053—Skin, nerves, brain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/50—Fusion polypeptide containing protease site
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/16011—Herpesviridae
- C12N2710/16111—Cytomegalovirus, e.g. human herpesvirus 5
- C12N2710/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
Definitions
- the present invention relates to immunotherapeutic agents.
- it relates to agents that can be used to prevent or treat a condition characterised by the presence of unwanted cells, such as tumours or other disease causing cells.
- Immunotherapeutic strategies for targeting malignant disease are an active area of translational clinical research, and have been for several decades.
- the current models dictate that cancer represents either a functional or constitutional immunodeficiency which can be treated with immunotherapeutic manipulation of the host.
- These efforts can be broadly classified into 2 groups.
- the first serves to augment or support endogenous anti-tumour immunity through measures such as vaccination, cytokine support (IL-2, IFN ⁇ ) or reducing immunosuppressant environment (ipilimumab) whilst the second seeks to restore an absolute deficiency with components of a functional immune response (passive immunotherapy with antibodies, TCR transfer, Stem Cell Transplantation and adoptive immunotherapy).
- cytotoxic therapeutic antibodies rely on immunological effector mechanisms to deliver their anti-cancer effect such as complement dependent cytotoxicity (CDC) and Antibody Dependent Cellular Cytotoxicity (ADCC).
- CDC complement dependent cytotoxicity
- ADCC Antibody Dependent Cellular Cytotoxicity
- all cells both healthy and malignant have numerous mechanisms to limit attack by the immune response to avert autoimmunity. This is evident in the context of autoimmune disease where high levels of tissue-reactive antibodies, which although frequently evoke organ inflammation, rarely induce complete organ destruction. Indeed, autoimmune diseases where complete tissue destruction is observed, such as diabetes mellitus, are known to be dependent on CTL responses rather than antibody-directed mechanisms.
- ADCs antibody-drug conjugates
- ADCs generally comprise a monoclonal antibody against a target present on a tumour cell, a cytotoxic drug, and a linker that attaches the antibody to the drug.
- ADCs are currently in the late stage of clinical development, and of those that are, clinical success has proven elusive.
- WO 95/17212 describes conjugates consisting of peptidic T cell antigens and cell binding partners and their use in re-directed immunotherapy.
- the conjugates comprise a binding partner with selectivity for target cells and a T cell antigen, and are said to induce specific cytotoxicity of T cells in the treatment of cancer, autoimmune diseases, diabetes or allergic diseases.
- the conjugates are said to be internalised into target cells following binding of the binding partner to surface receptors, and the T cell antigen is processed from the conjugate and expressed on the cell surface in the form of a complex with MHC molecules. Cytotoxicity of T cells for the target cells is thereby induced.
- MHC Class-I pathway An advantage of the MHC Class-I pathway is that, unlike MHC Class-II molecules, MHC Class-I molecules are present on all cell types.
- FIG. 1 MDA.MB.231 cells transduced with MMP14 stained with Cetuximab conjugated to NLVPMVATV (SEQ ID No: 21) containing MMP14 cleavage sequence (NLVPMVATVLPRSAKELRC (SEQ ID No: 280) linked to Cetuximab using Sulpho-SMCC).
- NLVPMVATV SEQ ID No: 21
- NLVPMVATVLPRSAKELRC SEQ ID No: 280
- FIG. 2 B-LCL cells stained with Rituximab conjugated to the HLA class-II peptide DYSNTHSTRYV (SEQ ID No: 55) containing a protease cleavage sequence (DDYSNTHSTRYVTIPVSLRSGGGGSGGGGSC) (SEQ ID No: 274).
- FIG. 3 B-LCL cells stained with Rituximab conjugated to the HLA class-I peptide TPRVTGGGAM (SEQ ID No: 31) containing a protease cleavage sequence (KTPRVTGGGAMAIPVSLRSGGGGSGGGGSC) (SEQ ID No: 273) linked to Rituximab using Sulpho-SMCC.
- TPRVTGGGAM HLA class-I peptide
- KTPRVTGGGAMAIPVSLRSGGGGSGGGGSC protease cleavage sequence linked to Rituximab using Sulpho-SMCC.
- FIG. 4 (A) Schematic diagram of an exemplary embodiment of the invention. (B) Schematic showing design and mechanism of viral peptide delivery. (i) Preferred targeting molecule consisting of a monoclonal antibody able to target a tumour cell, covalently linked to a synthetic peptide containing a protease recognition domain and a T cell peptide antigen. (ii) The peptide-conjugate is delivered to the target cell via a specific antibody and the peptide is cleaved in the proximity of the tumour cell. The released smaller viral peptide is passively binds to empty to empty MHC class I or II molecules on the cell surface. The MHC-peptide complexes are then recognised and by specific circulating T-cells mediating tumour cell-lysis.
- Preferred targeting molecule consisting of a monoclonal antibody able to target a tumour cell, covalently linked to a synthetic peptide containing a protease recognition domain and a T cell peptide antigen.
- FIG. 5 In vitro activity of redirected virus-specific T cells.
- A Recognition of a lymphoblastoid lymphoma cell lines by CD8 + cytomegalovirus-specific cytotoxic T lymphocytes through conjugation of the cognate antigen TPRVTGGGAM (SEQ ID No: 31) peptide to Rituximab (anti-CD20). Recognition is only present if the peptide is flanked by the MMP2 cleavage motif. Controls are tumour cells alone, CTLs alone and tumour cells pulsed with free TPR peptide (KTPRVTGGGAMAIPVSLRSGGGGSGGGGSC) (SEQ ID No: 273) linked to Rituximab using Sulpho-SMCC.
- TPRVTGGGAMAIPVSLRSGGGGSGGGGSC free TPR peptide
- Tumour cells were then incubated overnight with DYSN-specific CD4 + T cells and T cell recognition determined using IFN ⁇ release by ELISA.
- the inclusion of a protease cleavage site adjacent to the DYSN peptide dramatically increases recognition of the tumour cells by CD4 + T cells.
- C Application toward breast carcinoma cell line MDA-MB231 using cytomegalovirus-specific CD8 + CTL specific for cytomegalovirus pp65 (NLVPMVATV) (SEQ ID No: 21) epitope.
- Conjugation of the peptide combined with a MMP14 cleavage site mediates killing of the cells (NLVPMVATVLPRSAKELRC; SEQ ID No: 280) linked to Cetuximab using Sulpho-SMCC. Further data not shown indicates that a peptide conjugate lacking the MMP14 cleavage site shows killing comparable to Cetuximab alone.
- FIG. 6 In vitro and in vivo targeting of tumour cell lines using APEC approach.
- A EGFR expression on two breast carcinoma cell lines MCF7 and MB-MDA231.
- B Successful targeting of EGFR+ cell line MDA-MB231 using NLVPMVATV (SEQ ID No: 21) peptide containing a protease cleavage site (CSGGGGSGGGGAIPVSLRANLVPMVATV; SEQ ID No: 276) conjugated to Cetuximab.
- NLVPMVATV SEQ ID No: 21
- CSGGGGSGGGGAIPVSLRANLVPMVATV SEQ ID No: 276
- MCF-7 which does not express EGFR is not targeted by Cetuximab immunoconjugate.
- the B-RPH is a HLA-mismatched peptide deigned to not be recognised by the T cells and the VLE-protease cleavage peptide is an HLA-matched peptide.
- This peptide is designed to be a control for the protease cleavage sequence to ensure that the T cells do not recognise a portion of the protease cleavage sequence.
- the response to the VLE-protease cleavage peptide is negligible, the response seen with the NLV-protease cleavage peptide is borne against the NLVPMVATV (SEQ ID No: 21) sequence and not the protease cleavage sequence.
- FIG. 7 In vivo targeting of tumour cell lines using APEC approach.
- A in vivo xenograft data demonstrating that the human MDA-MB-231 breast cancer cell line can be eradicated by CMV-specific T cells when Cetuximab-peptide conjugates are given via intraperitoneal injection. Cetuximab-peptide complexes alone are unable to control the tumour growth (upper), whilst neither are CMV-specific T-cells (middle). However the combination of both cause eradication of this aggressive breast cancer tumour in vivo.
- B Successful targeting of colorectal cell line Colo205 using anti-Muc1 antibodies linked with CMV-specific T cell epitope and protease cleavage site.
- GP1.4 and SM3 are well-characterised anti-MUC1 specific antibodies.
- This anti-Muc1 antibody-peptide conjugate also very efficiently targets pancreatic carcinoma cell line Panc1.
- MH1, SM3 and GP1.4 are all well-characterised MUC1-specific monoclonal antibodies.
- MH1 is specific for the cytoplasmic tail of MUC1 and therefore does not bind to intact tumour cells, whereas, SM3 and GP1.4 bind to the extracellular portion of MUC1 glycoprotein.
- the peptide used is the NLV peptide using the reverse sequence (CSGGGGSGGGGAIPVSLRANLVPMVATV) (SEQ ID No: 276).
- the peptides are as follows NLVR (CSGGGGSGGGGAIPVSLRANLVPMVATV) (SEQ ID No: 276) containing the protease cleavage site, RNLV (RNLVPMVATVQIPVSLRSGGGGSGGGGSC) (SEQ ID No: 275) containing the same protease cleavage site as NLV-R and differing from NLV-R in the orientation of the viral epitope and the biotin peptide (Biotin-PFMRPHERNGFTVLC: SEQ ID No: 320) which does not contain the protease cleavage sequence and is used as a control peptide.
- NLVR CSGGGGSGGGGAIPVSLRANLVPMVATV
- RNLV RNLVPMVATVQIPVSLRSGGGGSGGGGSC
- Biotin-PFMRPHERNGFTVLC SEQ ID No: 320
- (D) Single chain fragment V (scFv) protein construct encoding for the same peptide sequence as used in (A) but contained within the scFv single polypeptide chain demonstrates activity against MDA-MB-231 cell line in vitro.
- the protease recognition site within the ScFv construct is IPVSLRS (SEQ ID No: 310).
- FIG. 8 Plasma stability of the antibody-peptide conjugate and specific targeting of tumour B cells.
- A Recognition of a lymphoblastoid cell line or healthy B cells by CD8+cytomegalovirus specific cytotoxic T cells after labelling cells with Rituximab conjugated with MHC class I peptides derived from cytomegalovirus. There is no recognition of healthy B cells whereas there is recognition of target cells only in the presence of the viral peptide the T cells are specific for. This data demonstrates the specificity of the APEC for malignant cells compared with healthy tissue.
- B The antibody peptide-epitope conjugate (APEC) was incubated at 37° C.
- the peptide sequences used were NLV-Protease Cleavage-Reverse (CSGGGGSGGGGAIPVSLRANLVPMVATV) (SEQ ID No: 276) containing the protease cleavage site IPVSLRS (SEQ ID No: 310), VLE-Protease Cleavage (YVLEETSVMLIPVSLRSGGGGSGGGGSC) (SEQ ID No: 277) containing the protease cleavage site IPVSLRS (SEQ ID No: 310) and Biotin-RPH (Biotin-PFMRPHERNGFTVLC: SEQ ID No: 320) used as a control peptide without the protease cleavage sequence.
- CSGGGGSGGGGAIPVSLRANLVPMVATV NLV-Protease Cleavage-Reverse (CSGGGGSGGGGAIPVSLRANLVPMVATV) (SEQ ID No: 276) containing the protease cleavage site IPVSLRS (SEQ ID No:
- FIG. 10 (A) The dependency of external proteolytic activity: target cells are lightly fixed in paraformaldehyde or not and then incubated with either peptide (NLVPMVATV) (SEQ ID No: 21) or Cetuximab conjugated with either an irrelevant peptide (VLE) or cognate peptide (NLVPMVATV: SEQ ID No: 21-protease cleavage site) and incubated with NLVPMVATV (SEQ ID No: 21)-specific T-cells.
- NLVPMVATV peptide
- VLE irrelevant peptide
- NLVPMVATV SEQ ID No: 21-protease cleavage site
- FIG. 11 (A) Demonstration that cytokines can be used as targeting moiety with IL-2 (A) and IL-4 (B) being conjugated with HLA-class II peptide (DR7-restricted) PDDYSNTHSTRYVC (SEQ ID No: 309) and using the Biotin-RPH (Biotin-PFMRPHERNGFTVLC; SEQ ID No: 320) as a control peptide.
- A Demonstration that cytokines can be used as targeting moiety with IL-2 (A) and IL-4 (B) being conjugated with HLA-class II peptide (DR7-restricted) PDDYSNTHSTRYVC (SEQ ID No: 309) and using the Biotin-RPH (Biotin-PFMRPHERNGFTVLC; SEQ ID No: 320) as a control peptide.
- FIG. 12 T cell recognition by range of tumour cell lines. Eight HLA-A*0201 NCI-60 cell lines are all recognised by HLA-A*0201-restricted CMV-specific T-cells when pulsed with cognate antigen.
- FIG. 13 in vitro targeting of human carcinoma cell lines using antibody-peptide-epitope conjugate (APEC) approach.
- A Early data showing that Cetuximab-peptide conjugates could be used to target carcinoma cell lines. Positive control is cognate viral peptide pulsed tumours—as in FIG. 12 .
- B The introduction of a protease cleavage site in the peptide is critical for effective targeting of tumour cells. Peptides not bearing a cleavage sequence (PC) are not cleaved and therefore not recognised by T-cells.
- PC cleavage sequence
- C Using Cetuximab-MMP2-NLVPMVATV (SEQ ID No: 21) APEC we can successfully target 4 out of 7 HLA-A*0201 NCI-60 cell lines. NCI-H522 and Colo205 are also weakly recognised, whereas HCT-116 is not recognised. Caki-2 is not HLA-A*0201 and serves only as a control.
- D We have produced scFv protein based upon Cetuximab sequence and N-terminally linked MMP2-NLVPMVATV (SEQ ID No: 21). This agent is also able to target MDA-MB-231 tumour cells in vitro (shown in red).
- E Assessment of in vitro potency of Cetuximab APEC.
- NLVPMVATV NLVPMVATV
- the peptides used were CSGGGGSGGGGAIPVSLRANLVPMVATV (SEQ ID No: 276) (‘NLVPMVATV-PC’) that contains the protease cleavage sequence AIPVSLR (SEQ ID No: 313), and CSGGGGSGGGGANLVPMVATV (SEQ ID No: 315) (‘NLVPMVATV’) that does not contain a protease cleavage site.
- FIG. 14 (A) Immunohistochemistry of 4 human adenocarcinomas showing CD8+ T cells by immunohistochemistry reveal abundant CD8+ T-cell infiltrate in human carcinomas. (B) Using Anti-Muc1(SM3)-(Protease Cleavage)-NLVPMVATV (SEQ ID No: 21) APEC we can successfully target the pancreatic carcinoma cell line Panc-1. (C) Using Rituximab-Protease Cleavage)-NLVPMVATV (SEQ ID No: 21) APEC we can differentially target a model tumour B cell line (LCLs) (black bars) and avoid targeting healthy B cells (white bars).
- LCLs model tumour B cell line
- ‘U266+NLVPMVATV (SEQ ID No: 21)+T cell’ corresponds to the native 9 amino acid peptide alone as a free peptide epitope (i.e. no linker etc), and serves as a positive control as it is essentially the maximum possible response.
- FIG. 21 ‘U266+NLVPMVATV (SEQ ID No: 21)+T cell’ corresponds to the native 9 amino acid peptide alone as a free peptide epitope (i.e. no linker etc), and serves as a positive control as it is essentially the maximum possible response.
- NLVPMVATV NLVPMVATV
- the peptides used were CSGGGGSGGGGAIPVSLRANLVPMVATV (SEQ ID No: 276) (‘NLVPMVATV-PC’) that contains the protease cleavage sequence AIPVSLR (SEQ ID No: 313), and CSGGGGSGGGGANLVPMVATV (SEQ ID No: 315) (‘NLVPMVATV’) that does not contain a protease cleavage site.
- the agents of the invention are an example of re-directed immunotherapy. This refers to the concept of re-directing an existing immune response that normally target cells harbouring foreign antigens, to target unwanted cells in conditions such as cancer. The concept requires the presentation of marker antigens on unwanted cells such that they become a target for immune cells.
- the agents of the present invention aim to circumvent all of the above problems whilst improving specificity, and exploit the fact that T cell antigens can be presented without first being internalised into a cell and being engaged in the classical antigen processing pathways.
- T cell antigens can be presented without first being internalised into a cell and being engaged in the classical antigen processing pathways.
- MHC Class-I processing pathway which continuously feeds peptides from the intracellular compartment via targeted intracellular proteolysis by the proteosome, peptide transport through the TAP and MHC Class-I peptide loading within the ER
- antigens can also be presented without internalisation. This less directed mechanism relies on a short half-life of some MHC Class-I associated peptides due to low affinity of some MHC bound peptides to the MHC molecule.
- T cell antigens e.g. peptides
- T cell antigens can bind to MHC Class-II molecules and the present invention also circumvents the Class-II antigen processing pathway to directly load antigens at the cell membrane.
- Group I CD1 molecules CD1a, CD1b and CD1c have been shown to present lipids to both cytotoxic alpha beta T cells as well as cytotoxic gamma delta T cells (Porcelli et al (1989) Nature, 341, 447-450).
- the inventors have found that by introducing a cleavage site in close proximity to the T cell antigen, which cleavage site is selectively cleaved in the vicinity of the unwanted cells, the T cell antigen can be liberated from a targeting moiety in the vicinity of the unwanted cells and can become bound by, for example, empty MHC molecules or Group I CD1 molecules, and elicit a T cell response.
- the agent can target cells expressing MHC Class-I molecules compared to only MHC Class-II expressing cells as in WO 95/17212; and specificity is increased by virtue of the cleavage site only being cleaved in the vicinity of the unwanted cells.
- tumour cells secrete proteases that are required by tumours for invasion of local tissues and metastasis, and so by including a tumour-specific protease cleavage site in the agent, the specificity of the agent for the tumour is increased.
- cleavage site to bypass the requirement for internalisation and classical processing in order for T cell antigens to be efficiently presented to T cells is a key advantage of the invention.
- the presence of the cleavage site means that all cells become amenable to re-directed immunotherapy, and not just the relatively small population of antigen presenting cells that express MHC Class II molecules. This is especially important for tumours where most tumour cells do not express MHC Class II molecules.
- the cleavage site also circumvents the challenges involved in ensuring that T cell antigens are not only successfully internalised, but that they correctly enter the appropriate cellular processing pathway to be presented on the cell surface.
- the cleavage site By by-passing the need for internalisation, the cleavage site further provides the ability to target neighbouring tumour cells and stromal non-malignant tissue such as tumour-fibroblasts of blood vessels. It also circumvents tumour-evasion mechanisms that operate in classical antigen processing. All in all therefore, the cleavage site provides for a simpler and more effective method of re-directing immunotherapy to more cell types.
- the targeting moiety of the agent functions to bring a T cell antigen directly into the vicinity of an unwanted cell.
- the unwanted cell may then present the T cell antigen, once cleaved from the targeting moiety, on its surface such that the unwanted cell becomes a target for an existing T cell response. This allows for the redirection of an existing immune response to the unwanted cell directly, and so no co-stimulation by antigen presenting cells (APCs) is necessary.
- APCs antigen presenting cells
- Cross-presentation refers to the mechanism by which an antigen is transferred to a professional APC which, in turn, presents it on an MHC Class I molecule to a na ⁇ ve T cell so as to generate a primary cytotoxic T cell response specific for that antigen.
- the process is important in the activation of na ⁇ ve T cells which must first recognise class I-associated peptide antigens and also encounter costimulators on APCs, or signals provided by helper T cells.
- APCs as opposed to unwanted cells are targeted so that APCs may co-stimulate cytotoxic T cells and thereby generate a new immune response.
- WO 2008/019366 discusses attaching antigens to a particle that can be phagocytosed by APCs such that the antigen can be released in the phagosome of the APC and thereby be cross-presented onto MHC Class I molecules.
- EP 1 948 802 describes attaching an antigen to an antibody Fc fragment so as to promote internalisation of the antigen into the APC.
- targeting of antigens to unwanted cells rather, the antigen is targeted to a specialised subset of APCs which, in turn, activate cytotoxic T cells to kill unwanted cells.
- none of the documents describe the use and redirection of an existing immune response nor do they disclose that the T cell antigen can be presented on the surface of a cell without the need for internalisation.
- a first aspect of the invention provides an agent for preventing or treating a condition characterised by the presence of unwanted cells, the agent comprising (i) a targeting moiety that is capable of targeting to the unwanted cells; and (ii) a T cell antigen, wherein the T cell antigen can be released from the targeting moiety by selective cleavage of a cleavage site in the agent in the vicinity of the unwanted cells.
- targeting moiety we include the meaning of any moiety that is capable of targeting to the unwanted cells.
- the targeting moiety is capable of targeting selectively to the unwanted cells.
- the targeting moiety targets unwanted cells to a greater extent than it does normal cells, and most preferably targets only unwanted cells.
- binding of the targeting moiety to normal cells may be tolerated if they can be functionally replaced by other therapeutic means or if they are not essential to life.
- a targeting moiety that targets to a cancer cell as well as, for example, an endocrine tissue or organ is not precluded.
- the targeting moiety acts to redirect an immune response to both unwanted cells and to other cells that can be functionally replaced by therapeutic means.
- the tissue or organ may be sacrificed provided its function was either not essential to life, for instance in the case of the testes, prostate or pancreas, or could be supplied by hormone replacement therapy. Such considerations would apply to the thyroid gland, parathyroids, adrenal cortex and ovaries, for example.
- the targeting moiety may be a moiety that is capable of targeting selectively to unwanted cells as opposed to wanted cells, wherein the unwanted cells may include cells whose presence in a host is undesired and optionally cells whose presence in the host is desired but whose presence can be functionally replaced by therapeutic means.
- the targeting moiety targets selectively to unwanted cells as opposed to any other cells.
- the targeting moiety is a specific binding partner of an entity expressed by or associated with the unwanted cell.
- the expressed entity is expressed selectively on the unwanted cell.
- the abundance of the expressed entity is typically 10 or 100 or 500 or 1000 or 5000 or 10000 higher on the unwanted cell than on other cells within the body to be treated.
- the cleavage site provides additional specificity on where the T cell antigen is released and so the binding partner may bind an entity that is similarly or even underexpressed on unwanted cells relative to other cells within the body.
- binding partner we include the meaning of a molecule that binds to an entity expressed by a particular cell.
- the binding partner binds selectively to that entity.
- the binding partner has a K d value (dissociation constant) which is at least five or ten times lower (i.e. higher affinity) than for at least one other entity expressed by another cell (e.g. a normal cell type), and preferably more than 100 or 500 times lower.
- the binding partner of that entity has a K d value more than 1000 or 5000 times lower than for at least one other entity expressed by another cell (e.g. normal cell type).
- K d values can be determined readily using methods well known in the art.
- the binding partner may bind selectively to an entity expressed by an unwanted cell and by a normal cell provided that the normal cell may be functionally replaced or else is not essential to life.
- anti-CD20 which targets all B cells
- B cells healthy and malignant.
- this can be tolerated as B cells are not critical for health.
- melanoma lymphoma, prostate cancer, thyroid, testicular or ovarian cancer, targeting healthy counterpart tissue would also be tolerated.
- the binding partner is one that binds to an entity that is present or accessible to the binding partner in significantly greater concentrations in or on unwanted cells than in any normal cells of the host.
- the binding partner may bind to a surface molecule or antigen on the unwanted cell that is expressed in considerably higher amounts than on normal cells.
- the binding partner may bind to an entity that has been secreted into the extracellular fluid by the unwanted cells to a greater extent than by normal cells.
- the binding partner may bind to a tumour associated antigen which is expressed on the cell membrane or which has been secreted into tumour extracellular fluid.
- the targeting moiety may be any of a polypeptide, a peptide, a small molecule or a peptidomimetic.
- the targeting moiety is an antibody that binds to an antigen expressed by the unwanted cell.
- Preferred antibody targets include: Her2/Neu (Epithelial malignancies); CD22 (B cells, autoimmune or malignant); EpCAM (CD326) (Epithelial malignancies); EGFR (epithelial malignancies); PMSA (Prostate Carcinoma); CD30 (B cell malignancies); CD20 (B cells, autoimmune, allergic or malignant); CD33 (Myeloid malignancies); membrane IgE (Allergic B cells); IgE Receptor (CD23) (Mast cells or B cells in allergic disease), CD80 (B cells, autoimmune, allergic or malignant); CD86 (B cells, autoimmune, allergic or malignant); CD2 (T cell or NK cell lymphomas); CA125 (multiple cancers including Ovarian carcinoma); Carbonic Anhydrase IX (multiple cancers including Renal Cell Carcinoma); CD70 (B cells
- Particularly preferred antibodies include an anti-epidermal growth factor receptor antibody such as Cetuximab, an anti-Her2 antibody, an anti-CD20 antibody such as Rituximab, an anti-CD22 antibody such as Inotuzumab, an anti-CD70 antibody, an anti-CD33 antibody such as hp67.6 or Gemtuzumab, an anti-MUC1 antibody such as GP1.4 and SM3, an anti-CD40 antibody, an anti-CD74 antibody, an anti-P-cadherin antibody, an anti-EpCAM antibody, an anti-CD138 antibody, an anti-E-cadherin antibody, an anti-CEA antibody, and an anti-FGFR3 antibody.
- an anti-epidermal growth factor receptor antibody such as Cetuximab, an anti-Her2 antibody, an anti-CD20 antibody such as Rituximab, an anti-CD22 antibody such as Inotuzumab, an anti-CD70 antibody, an anti-CD33 antibody such as hp67.6 or Gemtu
- tumour-associated, immune cell-associated and infection reagent-related antigens which may be targeted by the targeting moiety are given in Table 1.
- Tumour Associated Antigens Carcino-embryonic C46 (Amersham) Imaging and therapy Antigen 85A12 (Unipath) of colon/rectum tumours. Placental Alkaline H17E2 (ICRF, Imaging and therapy Phosphatase Travers & Bodmer) of testicular and ovarian cancers. Pan Carcinoma NR-LU-10 (NeoRx Imaging and therapy Corporation) of various carcino- mas including small cell lung cancer. Polymorphic HMFG1 (Taylor- Imaging and therapy Epithelial Mucin Papadimitriou, of ovarian cancer and (Human milk fat ICRF) pleural effusions.
- ICRF Imaging and therapy Phosphatase Travers & Bodmer
- the targeting moiety may be any compound or part thereof that specifically binds, in a non-immune sense, to an entity expressed by unwanted cells or otherwise becomes associated with the unwanted cells.
- the specific binding partner may be any of a hormone, a growth factor, a cytokine, or a receptor ligand (e.g. agonist or antagonist).
- cytokines have previously been used to target toxins to invading bacterial.
- recombinant proteins have been produced which contain for example IL-2 and a binding domain-deleted Pseudomonas exotoxin protein (Lorderboum-Galski et al, 1988 (62)). This immunotoxin was effective in experimental animal models (Kozak et al, 1990 (63)). Fusion proteins have also been produced with IL-4, IL-6, alpha-MSH, EGF and TNF-alpha (reviewed in Waldmann 1992 (35)), all of which are appropriate for use as targeting moieties in the present invention.
- Particularly useful targeting moieties include cytokines such as IL-2, EGF, VEGF, Flt3L, HGF, IGF, IL-6, or IL-4.
- IL-2 and IL-4 can target to adult T cell leukaemia/lymphoma cells which express the high affinity IL-2 receptor whereas normal resting T-cells do not, or to T-cells expressing the IL-4 receptor.
- the monoclonal antibody MR6 which binds to the human IL-4 receptor, can inhibit the IL-4 induced proliferation of cloned helper T cells and the production of IgE by polyclonal B cells (Larche et al, 1988 (36)).
- Such targeting moieties may be used to eliminate a lymphoid cell subpopulation in autoimmune disease or allergy.
- IGF-1 and IGF-11 Insulin like growth factors are preferentially taken up by malignant cells and so may be used to target tumour cells.
- EGF can be used to target malignant cells which upregulate the EGF receptor.
- tumour associated blood vessels overexpress VEGF receptor and so can be targeted by the family of VEGF growth factors.
- Flt3 receptor is overexpressed in leukaemias and may be a therapeutic target for acute and chronic leukaemias and myeloproliferative disorders.
- Myeloma cells express IL-6 receptor and also secrete IL-6 which acts in an autocrine fashion to stimulate cell proliferation.
- IL-6 may be used as a targeting moiety for myeloma.
- the targeting moiety is melanoma stimulating hormone (MSH) which binds to the MSH receptor which is expressed in high numbers in melanoma cells.
- MSH melanoma stimulating hormone
- a plurality of such antibodies has become commercially available.
- Other methods of identifying suitable binding partners for a given unwanted cell include genetic approaches (eg microarray), proteomic approaches (eg differential Mass spectrometry), immunological approaches (eg immunising animals with tumour cells and identifying antibody-secreting clones which specifically target malignant cells) and in silico approaches wherein targets are identified using a systems biology approach.
- CD52 T-cell lymphoma, T-cells and B-cell lymphomas Autoimmune induced immune cells may also be targeted.
- CD6 (Tp120) T-cell lymphoma, T-cells and B-cell lymphomas such as chronic lymphocytic leukaemia.
- CD70 tumor necrosis factor superfamily Lymphoma and many types of carcinoma member 7, TNFSF7, CD27LG, CD27L
- CD74 major histocompatibility class II invariant Lymphoma and many types of carcinoma chain, MH2
- CD80 B7-1, CD28LG1 Lymphoma and many types of carcinoma CD86 (B7-2, CD28LG2) Lymphoma and many types of carcinoma
- CEA anticarcinoembryonic antigen
- CEACAM3 carcinoembryonic antigen-related Many types of carcinoma, cell adhesion molecule 3, CGM1, CD66d
- CEACAM5 carcinoembryonic antigen-related Many types of carcinoma, cell adhesion molecule 5
- CEA, CD66e CEACAM8 (carcinoembryonic antigen-related Many types of carcinoma, cell adhesion molecule 8, NCA-95, nonspecific cross- reacting antigen 95 kDa, granulocyte cell antigen, CGM6, CD66b) ClfA
- CSF2 colony stimulating factor 2 (granulocyte- Myeloid diseases macrophage), granulocyte-macrophage colony stimulating factor, GM-CSF) CSF2RA (colony-stimulating factor Myeloid diseases 2(granulocyte-macrophage) receptor alpha subunit, GM-CSF-R-alpha, CD116)
- CSPG4 chondroitin sulfate proteoglycan 4, Many types of carcinoma, lymphoma, sarcoma high molecular weight-melanoma-associated and leukaemia antigen, HMW-MAA) CTLA4 (cytotoxic T lymphocyte-associated Regulatory T-cells and unwanted immune cells.
- ED-B fibronectin extra domain B
- EGFR epithelial growth factor receptor
- ERBB1 HER1, HER-1, ERBB
- EPCAM epithelial cell adhesion molecule
- epithelial glycoprotein 2 EGP-2
- epithelial cell adhesion molecule Ep- CAM, KSA, KS1/4 antigen, M4S, tumor antigen 17-1A, EpCAM, CD326
- ERBB2 epidermal growth factor receptor 2
- FCER2 immunoglobulin E Fc receptor low Many types of carcinoma, lymphoma, sarcoma affinity II, Fc epsilon RII, CD23) and leukaemia in B-cells.
- FCGR1 immunoglobulin G Fc receptor high Many types of carcinoma, lymphoma, sarcoma affinity I, Fc gamma RI, CD64, encoded by and leukaemia.
- human FCGR1A, FCGR1B, FCGR1C fibrin II beta chain (NH2 terminus) Many types of carcinoma, lymphoma, sarcoma and leukaemia.
- FLT1 (fms-related tyrosine kinase 1, vascular Many types of carcinoma, sarcoma, lymphoma, endothelial growth factor receptor 1, VEGFR-1, sarcoma and leukaemia. In particular tumour VEGFR, FLT, FRT, vascular permeability factor blood vessels. receptor) FOLH1 (folate hydrolase, prostate specific Many types of carcinoma, lymphoma, sarcoma membrane antigen, PSMA) and leukaemia in particular prostate carcinoma and unwanted prostate tissue.
- FOLR1 farnesoid receptor 1
- FOLR1 farnesoid receptor 1
- GD2 ganglioside Brain tumours and unwanted neuronal tissue GD3 ganglioside Brain tumours and unwanted neuronal tissue.
- GLP1R glucagon-like peptide 1 receptor
- GPNMB glycoprotein transmembrane NMB
- HGFIN hapten NP-cap (4-hydroxy-3-nitrophenacetyl
- HAVCR1 hepatitis A virus cellular receptor 1, Hepatitis A infected cells.
- HBV hepatitis B virus
- HBV infected cells HCMV (human cytomegalovirus)
- glycoprotein HCV hepatitis C virus
- HCV infected cells heat shock protein 90 homolog
- carcinoma, lymphoma, sarcoma and leukaemia HGF hepatocyte growth factor, scatter factor, Hepatoma and hepatocellular carcinoma.
- SF hepatopoeitin A
- HIV-1 human immunodeficiency virus HIV infected cells HLA-DR10 (DRB1*1001) Autologous or Allogeneic MHC Class-II expressing cells including tumour cells HLA-DRB (HLA-DR beta) Autologous or Allogeneic MHC Class-II expressing cells including tumour cells HSV (herpes simplex virus) HSV infected cells ICAM1 (intercellular adhesion molecule 1, Many types of carcinoma, lymphoma, sarcoma ICAM-1, CD54) and leukaemia ICAM3 (intercellular adhesion molecule 3, Many types of carcinoma, lymphoma, sarcoma ICAM-3, CD50) and leukaemia Membrane Immunoglobulin IgE IgE secreting B-cells and Plasma cells (cuasing allergic disease).
- IgE Fc IgE secreting B-cells and Plasma cells (cuasing allergic disease).
- IGF1R insulin-like growth factor 1 receptor, Most types of carcinoma, lymphoma, sarcoma IGF1-R, IGF-1R, CD221) and leukaemia IGHE connecting region (CO) M1 prime (in IgE secreting cells such as B-cells and plasma alternatively spliced heavy chain of membrane cells.
- IgE on B cells IL2RA (interleukin-2 receptor, alpha subunit, IL- B-cells and T-cells in either malignant or 2RA, TAC, CD25) autoimmune disease.
- IL2RB interleukin-2 receptor beta subunit, IL- B-cells and T-cells in either malignant or 2RB, p70, CD122
- IL5RA interteukin 5 receptor alpha subunit, B-cells and T-cells in either malignant or CD125
- IL6R interleukin 6 receptor, IL-6R, CD126
- ITGA2 ⁇ integrin alpha 2, GPIa subunit of the Many types of carcinoma, lymphoma, alpha2beta1 integrin (VLA-2, collagen leukaemias.
- ITGA2B_ITGB3 integrated with ITGA2B_ITGB3
- ITGA4 integrated with ITGA4 subunit, CD49d
- ITGA4_ITGB7 integrated with ITGA4_beta7, integrin Many types of carcinoma, lymphoma, ⁇ 4 ⁇ 7, lymphocyte Peyer's patch adhesion leukaemias.
- ITGA5 integrated molecule 1, LPAM-1) ITGA5 (integrin alpha 5 subunit, CD49e) Many types of carcinoma, lymphoma, leukaemias.
- ITGAE_ITGB7 integrated alphaE_beta7, integrin Many types of carcinoma, lymphoma, ⁇ E ⁇ 7, human mucosal lymphocyte antigen 1, leukaemias.
- HML-1) ITGAL integratedin alpha L subunit, lymphocyte Many types of carcinoma, lymphoma, function associated antigen 1, CD11a) leukaemias.
- ITGAV_ITGB3 (integrin alphaV_beta3, integrin Many types of carcinoma, lymphoma, ⁇ V ⁇ 3, CD51_GPIIIa, vitronectin receptor, VNR, leukaemias.
- CD51_CD61 ITGB1 (integrin beta1 subunit, GPIIa, CD29) Many types of carcinoma, lymphoma, leukaemias.
- ITGB2 (integrin beta2 subunit, LFA-1, MAC-1, Many types of carcinoma, lymphoma, CD18) leukaemias.
- KDR kinase insert domain receptor, vascular Many types of carcinoma, lymphoma, endothelial growth factor receptor 2, VEGFR2, leukaemias.
- LTA lymphotoxin alpha, TNF superfamily Many types of carcinoma, lymphoma, member 1, TNFSF1, LT) leukaemias.
- LTB lymphotoxin beta, TNF superfamily Many types of carcinoma, lymphoma, member 3, TNFSF3, p33) leukaemias.
- MET metal proto-oncogene, hepatocyte growth Many types of carcinoma, lymphoma, factor HGF receptor, HGFR, scatter factor SF leukaemias.
- MS4A1 membrane-spanning 4-domains Many types of carcinoma, lymphoma, subfamily A member 1, CD20) leukaemias.
- MSLN mesothelin, pre-pro-megakaryocyte- Many types of carcinoma, lymphoma, potentiating factor, megakaryocyte potentiating leukaemias. factor, MPF, CAK1
- MST1R microphage stimulating 1 receptor, Many types of carcinoma, lymphoma, macrophage stimulating protein receptor, MSP leukaemias.
- MSTN myostatin, growth differentiation factor Many types of carcinoma, lymphoma, 8, GDF8) leukaemias.
- MUC1 mimerase 1
- MUC1 sialylated carbohydrate, tumour- Many types of carcinoma, lymphoma, associated (CA242, cancer antigen 242) leukaemias.
- MUC16 (mucin 16, MUC-16, cancer antigen Many types of carcinoma, lymphoma, 125, CA125) leukaemias.
- MUC5AC (mucin 5AC, mucin 5 subtypes A and Many types of carcinoma, lymphoma, C tracheobronchial/gastric) leukaemias.
- N-glycolyl GM3 ganglioside (N- Brain tumours and unwanted neural tissue.
- glycolylneuraminic acid (NeuGc, NGNA) GM3 ganglioside, NeuGcGM3) NCA-90 (nonspecific cross-reacting antigens
- NCAM1 neural cell adhesion molecule 1
- NCAM-1 Brain tumours and unwanted neural tissue also NCAM-1, NCAM, CD56
- Nectin-4 Many types of carcinoma, lymphoma, sarcoma and leukaemia NGF (nerve growth factor, nerve growth factor Many types of carcinoma, lymphoma, sarcoma beta polypeptide, NGFB, beta-NGF) and leukaemia NIP-cap (3-iodo-4-hydroxy-5-nitrophenyl-acetyl Many types of carcinoma, lymphoma, sarcoma caproic acid) and leukaemia NRP1 (neuropilin 1, NRP, vascular endothelial Many types of carcinoma, lymphoma, sarcoma cell growth factor 165 receptor, VEGF165 and leukaemia receptor, VEGF165R, CD304) PDGFRA (platelet-derived growth factor Many types of carcinoma, lymphoma, sarcoma receptor alpha subunit, PDGFR2, CD140a) and leukaemia phosphatidylserine Many types of carcinoma, lymphoma, sarcoma and leukaemia
- PSCA prostate stem cell antigen
- RSV human respiratory syncytial virus, RSV infected cells glycoprotein F
- RTN4 reticulon 4, neurite outgrowth inhibitor
- SDC1 syndecan-1, CD138
- SELE E-selectin, CD62E
- SELL L-selectin, CD62
- SELP P-selectin, CD62
- SFRP1 selected frizzled-related protein 1, Many types of carcinoma and lymphoma.
- fusion regulatory protein 1, FRP-1) SLAMF7 (SLAM family member 7, CD2 subset Many types of unwanted cells including tumour 1, CS1, CD2-like receptor-activating cytotoxic cells and those involved in autoimmune cells, CRACC, 19A24, CD319) disease.
- SLC3A2 concentrate carrier family 3 (activators of Many types of unwanted cells including tumour dibasic and neutral amino acid transport) cells and those involved in inflammatory member 2, 4F2 antigen heavy chain, 4F2HC, disease.
- TGFB1 transforming growth factor beta1, TGF Many types of unwanted cells including tumour beta) cells and those involved in fibrotic disease.
- TGFB2 transforming growth factor beta 2
- TNF tumor necrosis factor
- TNFSF2 tumor necrosis factor
- TNFA tumor necrosis factor
- TNFRSF10A tumour necrosis factor receptor
- TNFR tumour cell superfamily member 10A
- DR4 TNF-related apoptosis- disease.
- TNFRSF10B tumor necrosis factor receptor
- TNFRSF10B tumor necrosis factor receptor
- TNFRSF10B tumor necrosis factor receptor
- TNFRSF12A tumor necrosis factor receptor
- TNFR tumour
- FGF inflammatory growth factor
- Fn14 TNF-like weak inducer of apoptosis (Tweak) receptor
- Tweak receptor Tweak receptor
- TweakR Tweak receptor
- TweakR TweakR
- CD30 tumor necrosis factor receptor
- TNFRSF9 tumor necrosis factor receptor
- tumour TNFR
- 4-1BB T cell cells and those involved in inflammatory and antigen ILA, CD137 autoimmune disease.
- TNFSF11 tumor necrosis factor (TNF)
- tumour superfamily member 11 tumour superfamily member 11
- osteoclast cells and those involved in inflammatory and differentiation factor, ODF, OPGL, RANKL
- TRANCE CD254
- TNFSF13 tumor necrosis factor (TNF)
- tumour superfamily member 13 a proliferation- cells and those involved in inflammatory and including ligand, APRIL, CD256 autoimmune disease.
- TNFSF13B tumor necrosis factor
- TNFSF14 tumor necrosis factor
- TNFSF4 tumor necrosis factor
- tumour superfamily member 4 OX40 ligand, OX-40L, cells and those involved in inflammatory and TAX transcriptionally-activated glycoprotein 1, autoimmune disease.
- TYRP1 tyrosinase-related protein 1, 5,6- Multiple carcinomas. dihydroxyindole-2-carboxylic acid oxidase, DHICA oxidase, TRP1, melanoma antigen gp75
- VAP-1 vascular adhesion protein
- VEGFA vascular endothelial growth factor A, Multiple carcinomas and hepatomas.
- VEGF-A, VEGF VIM (vimentin) Multiple carcinomas and hepatomas.
- antibody includes but is not limited to polyclonal, monoclonal, chimeric, single chain, Fab fragments, fragments produced by a Fab expression library and bispecific antibodies.
- fragments include fragments of whole antibodies which retain their binding activity for a target substance, Fv, F(ab′) and F(ab′)2 fragments, as well as single chain antibodies (scFv), fusion proteins and other synthetic proteins which comprise the antigen-binding site of the antibody.
- a targeting moiety comprising only part of an antibody may be advantageous by virtue of optimising the rate of clearance from the blood and may be less likely to undergo non-specific binding due to the Fc part.
- dAbs domain antibodies
- diabodies camelid antibodies
- engineered camelid antibodies the antibodies and fragments thereof may be humanised antibodies, which are now well known in the art (Janeway et al (2001) Immunobiology., 5th ed., Garland Publishing); An et al (2009) Therapeutic Monoclonal Antibodies : From Bench to Clinic, ISBN: 978-0-470-11791-0).
- asymmetric IgG-like antibodies eg triomab/quadroma, Trion Pharma/Fresenius Biotech; knobs-into-holes, Genentech; Cross MAbs, Roche; electrostatically matched antibodies, AMGEN; LUZ-Y, Genentech; strand exchange engineered domain (SEED) body, EMD Serono; biolonic, Merus; and Fab-exchanged antibodies, Genmab
- symmetric IgG-like antibodies eg dual targeting (DT)-Ig, GSK/Domantis; two-in-one antibody, Genentech; crosslinked MAbs, karmanos cancer center; mAb 2 , F-star; and Cov X-body, Cov X/Pfizer
- IgG fusions eg dual variable domain (DVD)-Ig, Abbott; IgG-like bispecific antibodies, Eli Lilly; Ts2Ab, Medimmune/AZ; BsAb, ZymoGenetics;
- the antibody may possess any of the antibody-like scaffolds described by Carter (2006) “Potent antibody therapeutics by design”, Nat Rev Immunol. 6(5): 343-57, and Carter (2011) “Introduction to current and future protein therapeutics: a protein engineering perspective”, Exp Cell Res. 317(9): 1261-9. incorporated herein by reference, together with the specificity determining regions described herein.
- the term “antibody” also includes affibodies and non-immunoglobulin based frameworks. Examples include adnectins, anticalins, affilins, trans-bodies, darpins, trimerX, microproteins, fynomers, avimers, centgrins and kalbitor (ecallantide).
- antibody fragments rather than whole antibodies
- the smaller size of the fragments may lead to improved pharmacological properties, such as better penetration of solid tissue.
- antigen-binding fragments such as Fab, Fv, ScFv and dAb antibody fragments can be expressed in and secreted from E. coli or yeast, thus allowing convenient production in the laboratory and economical production on a commercial scale.
- the antibody may be of any of the IgG, IgE, IgA, IgM and IgD classes and may be derived from any species. If the antibody is an IgG, it may be any of IgG1, IgG2, IgG3 or IgG4. It is preferred, however, that when the agent is for administration to a particular host, that the antibody, or at least the constant regions thereof, are derived from that host. For example, when the agent is to be administered to a human, the antibody is preferably a human antibody or a humanized antibody, and so on.
- Suitable antibodies that bind to particular antigens expressed by unwanted cells can be made by the skilled person using technology long-established in the art.
- Methods of preparation of monoclonal antibodies and antibody fragments are well known in the art and include hybridoma technology (Kohler & Milstein (1975) “Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256: 495-497); antibody phage display (Winter et al (1994) “Making antibodies by phage display technology.” Annu. Rev. Immunol. 12: 433-455); ribosome display (Schaffitzel et al (1999) “Ribosome display: an in vitro method for selection and evolution of antibodies from libraries.” J. Immunol.
- the targeting moiety may be a non-specific molecule that is capable, following administration to a subject, of accumulating in the vicinity of the unwanted cells.
- macromolecules accumulate non-specifically in tumours.
- Macromolecules known to accumulate in tumours non-specifically include albumin, immunoglobulins, transferrin, liposomes, nanoparticles (eg colloidal nanoparticles) and biodegradable polymers including dextrans, polyethylene glycol, polylysine and hydroxypropylmethylacrylamide.
- Macromolecules accumulate in human xenografted tumours in nude mice up to about 2.0% of administered dose per gram of tumour.
- Macromolecules such as polyethylene glycol and dextrans have been found to modify the clearance rate of substances to which they are attached and modify their concentration in tumours (Melton et al, 1987; Eno-Ammoquaye et al, 1996). In exceptional tumours, a non-specific macromolecule may accumulate in greater concentration than an antibody directed at the secreted antigen (Searle et al, 1981).
- EPR Enhanced Permeability and Retention
- the targeting moiety may be any of these macromolecules which accumulate in tumours.
- the macromolecule used in the invention is hydrophilic and is characterised by being soluble in body fluids and in conventional fluids for parenteral administration.
- the macromolecule is biodegradable so that systemic accumulation during repeated administration is avoided.
- the molecular weight and size of the agent comprising such a macromolecule targeting moiety exceeds that of the renal threshold for urinary excretion (MW 60 000), as this helps the blood concentration to be sufficient to provide an effective blood:tumour concentration gradient.
- a molecular weight of up to at least 800 000 is generally suitable, for example up to 160 000.
- the macromolecule is preferably one which is not readily captured by the reticuloendothelial system. The molecular weights given exclude any water of hydration.
- Macromolecules that are available as sub-units and are not biodegradable may be linked by biodegradable linking units so that the non-biodegradable components are filtered through the kidneys and excreted in the urine.
- the polymer used to make the macromolecule is not biodegradable such that the molecular weight of any non-biodegradable portion of the conjugate should be less than the renal threshold (circa 70000) so that after degradation of the biodegradable portion the residual non-biodegradeable portion is excreted through the kidneys.
- the macromolecule may be any of a dextran; a polyamino acid; a nanoparticle (eg colloidal nanoparticle), or a non-tumour-specific protein such as an immunoglobulin, an albumin or a transferrin.
- a dextran e.g colloidal nanoparticle
- a non-tumour-specific protein such as an immunoglobulin, an albumin or a transferrin.
- it may be a copolymer of styrene and maleic anhydride, or may be polyaspartic acid, poly-L-lysine, polyethyleneimine or polyethylene glycol.
- MDEPT melanocyte-directed enzyme prodrug therapy
- the unwanted cell may be any cell whose presence in a host is undesired.
- the cell may be a tumour cell (benign or malignant), a cell from a tumour microenvironment such as tumour fibroblasts or tumour blood vessels, a virally infected cell, a cell introduced as part of gene therapy, or a normal cell which one wishes to destroy for a particular reason.
- a subpopulation of immune cells such as T lymphocytes in autoimmune disease or such as B lymphocytes in allergic disease.
- a ‘condition characterised by the presence of unwanted cells’ we include any biological or medical condition or disorder in which at least part of the pathology is mediated by the presence of unwanted cells.
- the condition may be caused by the presence of the unwanted cells or else the presence of the unwanted cells may be an effect of the condition.
- examples of particular conditions include tumours (benign or malignant), autoimmune conditions, cardiovascular diseases, degenerative diseases, diabetes, allergic disease (eg asthma), neurodegenerative diseases such as Alzheimer's, transplantation patients and infectious diseases.
- the agent also has utility in regenerative medicine (eg laboratory grown organs or tissues). It is particularly preferred if the condition is a tumour (eg a malignant disease) and the unwanted cells are tumour cells or tumour associated tissue.
- the unwanted cells may represent cells of the adaptive or innate immune response, preferably T cells, but more preferably B cells.
- the unwanted cells may represent cells within atheromatous lesions such as macrophages.
- the unwanted cells may represent cells which induce the neurodegenerative changes, for instance in Alzheimer's disease they may be microglia or astrocytes.
- any cell which facilitates the process of degeneration or apoptosis may be considered a target.
- processes such as aging where unwanted tissue builds up, for example in benign prostatic hyperplasis non-malignant prostatic tissue would be a preferred target.
- tissue mast cells may be considered an ideal target, but also IgE secreting cells such as plasma cells or B cells.
- IgE secreting cells such as plasma cells or B cells.
- alloreactive lymphocytes would represent a preferred target cell.
- infectious disease any cell harbouring a virus, bacteria or fungal pathogen may be considered a preferred target cell for example an HIV infected cell.
- the unwanted cell is not an antigen presenting cell such as a professional antigen presenting cell with cross-presentation capability.
- T cell antigen we include the meaning of any antigen which can be presented to a T cell so as to elicit a T cell response.
- the T cell antigen may be presented to a T cell by an MHC molecule or by a Group I CD1 molecule. Once the antigen is presented on the surface of the cell, the cell is recognised as foreign and becomes the target of T cells, some of which have the natural function of eliminating foreign cells either infected by foreign organisms such as viruses, fungi, bacteria, mycobacteria or protozoa, or which have become cancerous (eg malignant).
- the T cell antigen may be one that is capable of being presented by a molecule on an unwanted cell.
- the T cell antigen may be presented on a cell other than an unwanted cell but still in the vicinity of an unwanted cell, and by virtue of subsequent T cell activation, an unwanted cell is killed, for example by local production of cytokines by activated T cells.
- Such indirect killing may be desirable, for example to target tumour blood vessels and/or stromal cells which support tumour growth.
- the T cell antigen is one that can elicit an existing T cell response in the subject to which the agent of the invention is administered.
- the T cell antigen is not one which generates a new primary T cell response for that antigen via cross-presentation in APCs.
- the T cell antigen is one to which a number of T cells in the subject are already sensitised to. Determining whether a subject's cells are sensitised to a given antigen can be done by contacting isolated peripheral mononuclear blood cells from the subject with the antigen and using standard assays for cell proliferation, as described further below and in the Examples.
- the agent of the invention is not one which generates a new T cell response specific for the T cell antigen contained in it.
- the invention includes an agent for preventing or treating a condition characterised by the presence of unwanted cells, the agent comprising (i) a targeting moiety that is capable of targeting to the unwanted cells; and (ii) a T cell antigen, wherein the T cell antigen can be released from the targeting moiety by selective cleavage of a cleavage site in the agent in the vicinity of the unwanted cells, and wherein the T cell antigen is capable of eliciting an existing T cell response in a subject.
- T cell we include all types of T cell including CD4+, CD8+, ⁇ T cells, and NK-T cells.
- the T cell is a cytotoxic T cell such that a cytotoxic T cell response is elicited.
- the mechanism of antigen presentation will depend upon the type of T cell.
- CD4+ T cells recognise peptide antigens bound to MHC Class II molecules
- CD8+ T cells recognise peptide antigens bound to MHC Class I molecules
- ⁇ T cells recognise small phosphorylated molecules, alkyl amines or lipids bound to group I CD1 molecules
- NK-T cells recognise lipid antigens bound to group I CD1 molecules. It is understood that any presentation route may be used provided that the antigen elicits a T cell response.
- the T cell antigen may be one that is capable of binding to an MHC Class I or MHC Class II molecule, or one that is capable of binding to a group I CD1 molecule.
- the T cell antigen is an immunodominant antigen (eg an antigen that elicits an existing immunodominant response).
- immunodominant we include the meaning that the antigen elicits a T cell response with high magnitude, sensitivity, tissue homing characteristics and efficiency in killing antigen bearing cells.
- an immunodominant response comprises more than 0.1% of a subject's CD8 + or CD4 + T cells. Determining the extent of a T cell response for a given antigen can be done for example by contacting isolated peripheral mononuclear blood cells from the subject with the antigen and using standard assays for cell proliferation known in the art.
- Suitable assays for determining the extent of an immune response include ELISpot, intracellular cytokine staining, HLA-peptide tetramer staining, proliferation assay, activation assays (eg CD69), CD107 mobilisation assays or metabolic assays (eg MTT).
- T cell antigens include any of a peptide, a polypeptide, a phosphopeptide or a lipid such as a phospholipid or a sphingolipid, and further examples of each of these are provided below.
- the T cell antigen When the T cell antigen is a peptide or polypeptide, typically it is one that is capable of being recognised by a T cell receptor when bound to an MHC molecule.
- the T cell antigen may be an MHC Class I restricted antigen that binds only to MHC Class I molecules, or it may be an MHC Class II restricted antigen that binds only to MHC Class II molecules. It is appreciated that the antigen may bind only to particular variant MHC Class I and/or MHC Class II molecules (e.g. natural variants found in particular subjects), or that the antigen may be capable of binding to any MHC Class I and/or MHC Class II molecule (i.e. the antigen is promiscuous).
- the T cell antigen is capable of binding to a MHC Class I molecule such as any of HLA-A, HLA-B and HLA-C. Since MHC Class I molecules are expressed on all cell types, this allows to agent of the invention to redirect an immune response to any unwanted cell.
- the peptide is capable of binding to HLA types A1, A2.1, A3.2, A11, A24, B7, B8, B35, B44, Cw1, Cw2, Cw3, Cw4 and Cw6 or mixtures thereof, which are believed to cover more than 90% of the Caucasian and Asian populations.
- the T cell antigen is capable of binding to a MHC Class II molecule such as any of HLA-DP, HLA-DQ or HLA-DR.
- MHC Class II types include DR1, DR3, DR4, DR7, DR52, DQ1, DQ2, DQ4, DQ8 and DP1.
- MHC Class II molecules are expressed on immune cells including antigen presenting cells such as dendritic cells, B cells and macrophages.
- the agent of the invention may be used to treat conditions such as lymphomas or autoimmune diseases.
- Another promiscuous peptide that may be used is the tetanus fragment C peptide.
- the T cell antigen is an immunogenic peptide that is recognised by an MHC molecule.
- Such peptides usually have a length of 9 to 22 amino acids (for recognition in the MHC Class II complex) or of 8 to 13 amino acids (for recognition in the MHC Class I complex).
- the peptide is an immunodominant peptide.
- immunodominant peptides include viral derived peptides that elicit endogenous anti-viral responses.
- the peptide may be derived from an endogenous virus such as Varicella-Zoster virus, Herpes simplex virus, cytomegalovirus, Epstein Barr virus, or influenza.
- Particularly preferred examples include peptides derived from human cytomegalovirus (CMV or Human herpesvirus 5/HHV5) or Epstein-Barr Virus (EBV or HHV4); herpesviruses such as HHV1, HHV2 and HHV3; influenza virus A; influenza virus B; rhinovirus; adenovirus; and Hepadnaviridae.
- HHV5 human cytomegalovirus
- the immunodominant antigens are well characterised (see Sylwester A W et al J Exp Med. 2005 Sep. 5; 202(5):673-85, incorporated herein by reference), and any such antigen described in Sylwester et al may be used in the present invention.
- Sylester et al synthesised consecutive 15mer peptides, overlapping by 10 amino acids, for 213 predicted human CMV proteins. This generated 13,687 peptides that were arranged in ORF or sub-ORF specific mixes.
- Peptides derived from ORFs UL55 (gB), UL 83 (pp65), UL 86, UL 99 (pp28), UL 122 (IE2), UL 36, UL 48, UL32 (pp150), UL 113, IRS-1, UL 123 (IE1), UL25, UL 141, UL 52 and UL 82 (pp71) were found to elicit the most CD 4+ T cell responses, and so it is particularly preferred if the peptide is derived from one of these ORFs.
- peptides derived from ORFs UL48, UL83 (pp66), UL 123 (IE1), UL 123 (IE2), US 32, UL 28, US 29, US3, UL 32 (pp150), UL 55 (gB), UL 94, UL 69, UL 105, UL 82 (pp71) and UL 99 (pp28) were found to elicit the most CD 8+ T cell responses, and so it is particularly preferred if the peptide is derived from one of these ORFs.
- cytomegalovirus T cell antigens are listed below.
- CD8+ T cell epitopes for cytomegalovirus antigens such as IE1 include YILEETSVM (SEQ ID No: 2), YVLEETSVM (SEQ ID No: 3), VLEETSVML (SEQ ID No: 4), VLAELVKQI (SEQ ID No: 5), ATTFLQTMLR (SEQ ID No: 6), EVISVMKRR (SEQ ID No: 7), CRVLCCYVL (SEQ ID No: 8), ELRRKMMYM (SEQ ID No: 9), ELKRKMIYM (SEQ ID No: 10), QIKVRVDMV (SEQ ID No: 11), CVETMCNEY (SEQ ID No: 12), RRKMMYMCY (SEQ ID No: 13), KRKMIYMCY (SEQ ID No: 14), RRIEEICMK (SEQ ID No: 15), DELRRKMMY (SEQ ID No: 16), KEVNSQLSL (SEQ ID No: 17),
- CD4+ T cell epitopes for cytomegalovirus antigens such as pp65 include PQYSEHPTFTSQYRIQ (SEQ ID No: 47), FTSQYRIQGKLEYRHT (SEQ ID No: 48), LLQTGIHVRVSQPSL (SEQ ID No: 49), NPQPFMRPHERNGFT (SEQ ID No: 50), EPDVYYTSAFVFPTK (SEQ ID No: 51), IIKPGKISHIMLDVA (SEQ ID No: 52), AGILARNLVPMVATV (SEQ ID No: 53), KYQEFFWDANDIYRI (SEQ ID No: 54); for gB they include DYSNTHSTRYV (SEQ ID No: 55), CMLTITTARSKYPYH (SEQ ID No: 56), and VFETSGGLVVFWQGI (SEQ ID No: 57); for 1E1 they include VRVDMVRHRIKEHMLKKYTQ (SEQ ID No: 58) and NYI
- CD8+ and CD4+ T cell epitopes identified in EBV lytic and latent cycle proteins (adapted from Hislop et al) CD8+ T cell epitopes EBV Epitope Epitope SEQ ID HLA Antigen coordinates sequence No restriction Latent cycle proteins EBNA1 72-80 RPQKRPSCI 61 B7 407-415 HPVGEADYF 62 B53 407-417 HPVGEADYFEY 63 B35.01 528-536 IPQCRLTPL 64 B7 574-582 VLKDAIKDL 65 A2.03 EBNA2 14-23 YHLIVDTDSL 66 B38 42-51 DTPLIPLTIF 67 A2/B51 234-242 RPTELQPTP 68 B55 EBNA3A 158-166 QAKWRLQTL 69 B8 176-184 AYSSWMYSY 70 A30.02 246-253 RYSIFFDY 71 A24 325-333 FLRGRAYGL 72 B8 378-387 KRP
- immunodominant peptides include HLA-A*0201-restricted epitopes (HCMV pp65 495-504—NLVPMVATV (SEQ ID No: 21), HCMV IE1 VLEETSVML (SEQ ID No: 4), EBV LMP-2 356-364 FLYALALLL (SEQ ID No: 127), EBV BMLF-1 259-267 GLCTLVAML (SEQ ID No: 155)); HLA-A*0101-restricted epitopes (HCMV pp50 245-253—VTEHDTLLY (SEQ ID No: 44); HCMV pp65 363-373—YSEHPTFTSQY) (SEQ ID No: 20); HLA-A*0301-restricted epitopes (HCMV pp50—TVRSHCVSK (SEQ ID No: 46),); HLA-B*0702-restricted epitopes (HCMV pp65 417-426 TPRVTGGGAM (SEQ ID No
- the T cell antigen may be one derived from a live vaccine such as Measles, Mumps, Rubella (MMR) or HHV3; or one derived from intracellular bacteria such as mycobacteria, particularly those evoked through immunization with BCG.
- a live vaccine such as Measles, Mumps, Rubella (MMR) or HHV3
- intracellular bacteria such as mycobacteria, particularly those evoked through immunization with BCG.
- the T cell antigen e.g. peptide
- the T cell antigen may be derived from the tetanus toxoid such as P2, P4 or P30.
- the T cell antigen e.g. peptide
- the T cell antigen may be one that elicits an existing immune response in a subject that has been generated by prior vaccination against an infectious agent.
- the subject may be vaccinated with a tetanus toxin, before being administered the agent of the invention comprising the relevant T cell antigen.
- the T cell antigen is one which is found in a childhood vaccine.
- the T cell antigen (eg peptide) may also be one that elicits an existing immune response in a subject that has been generated by exposing that subject's T cells to the antigen in vitro.
- Peptides can be produced by well known chemical procedures, such as solution or solid-phase synthesis, or semi-synthesis in solution beginning with protein fragments coupled through conventional solution methods as is known in the art.
- the peptide can be synthesised by established methods including recombinant methods.
- the T cell antigen is a polypeptide or peptide
- other antigens are also capable of eliciting immune responses and so have utility in the present invention.
- ⁇ T cells do not recognise MHC-associated peptide antigens and are not MHC restricted.
- Some ⁇ T cell clones recognise small phosphorylated molecules, pyrophosphorylated compounds (eg HMBPP (E-4-hydroxy-3-methyl-but-2-enyl-pyrophosphate) and IPP (isopentenyl pyrophosphate)), alkyl amines or lipids (e.g. phosphorylated lipids) that may be presented by ‘non-classical’ class I MHC-like molecules called CD1 molecules.
- NK-T cells e.g. V ⁇ 24V ⁇ 11 cells
- lipids e.g. ceramides such as ⁇ -gal-ceramide
- the T cell antigen may be any of these molecules that are known to elicit a T cell response.
- the T cell antigen may be an autoantigen or allergen respectively.
- the immune response that is contributing to the disorder is redirected to unwanted cells so as to combat the disorder.
- the T cell antigen may be chemically modified provided that it is still capable of eliciting a T cell response.
- Such chemical modification may include, for instance, the addition of a metal such as nickel, since it has been shown that in certain allergic patients there are T cells which recognise a peptide with a bound nickel atom (Romagnoli et al 1991, EMBO J 10: 1303-1306).
- the T cell antigen can also be modified by an organic molecule which enhances the immunogenicity (Romero et al 1993, J Immunol 150: 3825-3831).
- the T cell antigen is a peptide
- it may comprise naturally occurring amino acids encoded by DNA, and/or one or more non-natural amino acids, including amino acids in the “D” isomeric form, provided that it is recognised by the corresponding T cell.
- the peptide may be a peptide ‘mimetic’ ie peptidomimetic which mimics the structural features of any of the peptides mentioned above.
- the T cell antigen may be a retro-inverso peptide.
- the T cell antigen when a peptide, may be a mimotope, ie a peptide composed of natural or non-natural amino acids that mimics the structure of the natural epitope. Mimotopes often stimulate T cells more potently.
- the T cell antigens are substantially non-toxic in the absence of T lymphocytes.
- substantially non-toxic we mean that the antigens have considerably lower or preferably no detectable toxicity, compared to toxins such as Pseudomonas exotoxin.
- T cell antigens that may be used in the invention using the database available at www.immuneepitope.org (Vita R, Zarebski L, Greenbaum J A, Emami H, Hoof I, Salimi N, Damle R, Sette A, Peters B. The immune epitope database 2.0. Nucleic Acids Res. 2010 January; 38 (Database issue):D854-62. Epub 2009 Nov. 11).
- T cell antigen is released from the targeting moiety by means of a cleavage site between the T cell antigen and targeting moiety being cleaved selectively in the vicinity of the unwanted cells.
- cleavage site that is cleavable selectively in the vicinity of the unwanted cells we include the meaning of a site that can only be cleaved by a molecule which resides selectively in the vicinity of the unwanted cells, so as to release the T cell antigen from the targeting moiety.
- the molecule that cleaves the cleavage site resides in the vicinity of the unwanted cells at a concentration at least five times or ten times higher than the concentration of the molecule outside the vicinity of the unwanted cells, and more preferably at a concentration at least 100 or 500 or 1000 times higher.
- the molecule that cleaves the cleavage site is found only in the vicinity of the unwanted cells. For example, when the unwanted cells are particular tumour cells (e.g.
- the cleavage site may be one that is cleaved by a molecule which resides selectively in the particular tumour (e.g. breast tumour) but which molecule does not reside outside the vicinity of the particular tumour (e.g. breast tumour).
- the cleavage site is selectively cleaved outside of the unwanted cell, at or near its surface, so that the T cell antigen can be presented by the unwanted cell to T cells without needing to be internalised.
- the cleavage site is selectively cleaved in the vicinity of the unwanted cells so that the T cell antigen is preferentially presented by unwanted cells rather than by wanted cells.
- the cleavage site is one that is selectively cleaved such that the T cell antigen is released in the vicinity of (e.g. at or near to the cell surface) the unwanted cells at least five times or ten times more than the extent to which it is released in the vicinity of wanted cells, and more preferably at least 100 or 500 or 1000 times more.
- the T cell antigen is not released in the vicinity of wanted cells, and therefore not presented by wanted cells.
- the skilled person will be able to identify an appropriate cleavage site that is selectively cleavable in the vicinity of the unwanted cell, using established methods in the art. For example, which proteases cleave which peptides can be assessed by consulting peptide libraries and studying an MS analysis of the fragmentation profile following cleavage. Also, published literature of protease cleavage motifs and peptide cleavage data can be searched as described further below. Gene expression and proteomic data may also be analysed to identify which proteases are expressed by particular unwanted cells.
- the T cell antigen is selectively released in the vicinity of the unwanted cells.
- the inventors believe that this allows the unwanted cells to present the T cell antigen to T cells, thereby redirecting an existing immune response to the unwanted cells.
- the cleavage site is one that is cleaved in the vicinity of the unwanted cells and outside the unwanted cells, for example at the cell surface.
- the T cell antigen can be released in the vicinity of the external surface of the cell and presented to a T cell directly, without the need to be internalised and engage the appropriate processing pathways.
- the invention includes an agent for preventing or treating a condition characterised by the presence of unwanted cells, the agent comprising (i) a targeting moiety that is capable of targeting to the unwanted cells; and (ii) a T cell antigen, wherein the T cell antigen can be released from the targeting moiety by selective cleavage of a cleavage site in the agent in the vicinity of and outside of the unwanted cells.
- the T cell antigen is one which does not generate a new primary T cell response for that antigen, but rather elicits an existing T cell response in a subject.
- the T cell antigen may be released inside the cell, without the need to undergo classical antigen processing, and still be presented to a T cell.
- the cleavage site need not be cleaved at the surface of the cell but may be cleaved within the cell, for example via a receptor cycling pathway or in near-membrane compartments such as vesicles (e.g. pinocytic vesicles).
- the cleavage site may be one that is cleavable by an enzyme such as any of a protease, a nuclease, a lipase, a lyase, a phosphatase or a carbohydrase, which may or may not be membrane bound.
- an enzyme such as any of a protease, a nuclease, a lipase, a lyase, a phosphatase or a carbohydrase, which may or may not be membrane bound.
- the cleavage site is a protease cleavage site.
- the cleavage site may be cleavable selectively by proteases that reside in the vicinity of the tumour cells.
- the protease cleavage site may be one that is cleavable by a tumour associated protease. It is well known that during tumour development, tumours aberrantly express proteases which allow them to invade local tissues and eventually metastasise.
- the protease may include any of a cysteine protease (including the Cathepsin family B, L, S etc), an aspartyl protease (including Cathepsin D and E) and a serine protease (including Cathepsin A and G, Thrombin, Plasmin, Urokinase, Tissue Plasminogen Activator).
- the protease may be a metalloproteinase (MMP1-28) including both membrane bound (MMP14-17 and MMP24-25) and secreted forms (MMP1-13 and MMP18-23 and MMP26-28).
- the protease may belong to the A Disintegrin and Metalloproteinase (ADAM) and A Disintegrin, or Metalloproteinase with Thrombospondin Motifs (ADAMTS) families of proteases.
- ADAM A Disintegrin and Metalloproteinase
- ADAMTS Metalloproteinase with Thrombospondin Motifs
- Other examples include CD10 (CALLA) and prostate specific antigen (PSA). It is appreciated that the proteases may or may not be membrane bound.
- Protease cleavage sites are well known in the scientific literature, and linker sequences comprising such cleavage sites can be readily constructed using established genetic engineering techniques, or by synthetic synthesis techniques known in the art.
- the protease cleavage site may be one that is cleavable by any of the proteases listed in Table 4 below, which indicates the expression of selected proteases in various tumour types.
- Candidate substrates for the proteases are provided.
- the skilled person will typically select a protease cleavage site that is selectively cleaved by a protease known to be highly expressed in that tumour type, as seen from the table.
- Table 5 lists tumour sites in which ADAM protease overexpression has been reported, and so in an embodiment, the cleavage site is selectively cleavable by one of the ADAM proteases listed in Table 5. Accordingly, the agent may be used to prevent or treat the corresponding tumour type.
- the cleavage site may be selectively cleavable by any of the following human proteases (MEROPS peptidase database number provided in parentheses; Rawlings N. D., Morton F. R., Kok, C. Y., Kong, J. & Barrett A. J. (2008) MEROPS : the peptidase database. Nucleic Acids Res.
- pepsin A (MER000885), gastricsin (MER000894), memapsin-2 (MER005870), renin (MER000917), cathepsin D (MER000911), cathepsin E (MER000944), memapsin-1 (MER005534), napsin A (MER004981), Mername-AA034 peptidase (MER014038), pepsin A4 (MER037290), pepsin A5 ( Homo sapiens ) (MER037291), hCG1733572 ( Homo sapiens )-type putative peptidase (MER107386), napsin B pseudogene (MER004982), CYMP g.p.
- ADAMTS7 peptidase (MER005894), ADAM30 peptidase (MER006268), ADAM21 peptidase ( Homo sapiens -type) (MER004726), ADAMTS10 peptidase (MER014331), ADAMTS12 peptidase (MER014337), ADAMTS13 peptidase (MER015450), ADAM33 peptidase (MER015143), ovastacin (MER029996), ADAMTS20 peptidase ( Homo sapiens -type) (MER026906), procollagen I N-peptidase (MER004985), ADAM2 protein (MER003090), ADAM6 protein (MER047044), ADAM7 protein (MER005109), ADAM18 protein (MER012230), ADAM32 protein (MER026938), non-peptidase homologue ( Homo sapiens chromosome 4) (MER029973), family M12 non-peptidase
- chymopasin (MER001503), kallikrein-related peptidase 11 (MER004861), kallikrein-related peptidase 11 (MER216142), trypsin-2 type A (MER000021), HtrA1 peptidase ( Homo sapiens -type) (MER002577), HtrA2 peptidase (MER208413), HtrA2 peptidase (MER004093), HtrA3 peptidase (MER014795), HtrA4 peptidase (MER016351), Tysnd1 peptidase (MER050461), TMPRSS12 peptidase (MER017085), HAT-like putative peptidase 2 (MER021884), trypsin C (MER021898), kallikrein-related peptidase 7 (MER002001), matriptase (MER003735), kallikrein-related peptidase 13
- taspase-1 (MER016969), gamma-glutamyltransferase 5 (mammalian-type) (MER001977), gamma-glutamyltransferase 1 (mammalian-type) (MER001629), gamma-glutamyltransferase 2 ( Homo sapiens ) (MER001976), gamma-glutamyltransferase-like protein 4 (MER002721).
- gamma-glutamyltransferase-like protein 3 (MER016970). similar to gamma-glutamyltransferase 1 precursor ( Homo sapiens ) (MER026204).
- gamma-glutamyltransferase 1 precursor Homo sapiens ) (MER026205). Mername-AA211 putative peptidase (MER026207). gamma-glutamyltransferase 6 (MER159283). gamma-glutamyl transpeptidase homologue (chromosome 2, Homo sapiens ) (MER037241). polycystin-1 (MER126824), KIAA1879 protein (MER159329). polycystic kidney disease 1-like 3 (MER172554). gamma-glutamyl hydrolase (MER002963). guanine 5′′-monophosphate synthetase (MER043387).
- EGF-like module containing mucin-like hormone receptor-like 2 (MER037230). CD97 antigen (human type) (MER037286). EGF-like module containing mucin-like hormone receptor-like 3 (MER037288). EGF-like module containing mucin-like hormone receptor-like 1 (MER037278). EGF-like module containing mucin-like hormone receptor-like 4 (MER037294).
- EGF LAG seven-pass G-type receptor 2 precursor Homo sapiens ) (MER045397), Gpr64 ( Mus musculus )-type protein (MER123205).
- GPR56 Homo sapiens )-type protein (MER122057).
- latrophilin 2 (MER122199).
- latrophilin-1 (MER126380).
- latrophilin 3 (MER124612).
- protocadherin Flamingo 2 (MER124239).
- ETL protein (MER126267).
- G protein-coupled receptor 112 (MER126114). seven transmembrane helix receptor (MER125448).
- Gpr114 protein (MER159320).
- GPR126 vascular inducible G protein-coupled receptor (MER140015).
- GPR125 Homo sapiens )-type protein (MER159279).
- GPR116 Homo sapiens )-type G-protein coupled receptor (MER159280).
- GPR128 Homo sapiens )-type G-protein coupled receptor (MER162015).
- GPR133 Homo sapiens )-type protein (MER159334) GPR110 G-protein coupled receptor (MER159277), GPR97 protein (MER159322), KPG_006 protein (MER161773) KPG_008 protein (MER161835), KPG_009 protein (MER159335), unassigned homologue (MER166269), GPR113 protein (MER159352), brain-specific angiogenesis inhibitor 2 (MER159746), PIDD auto-processing protein unit 1 (MER020001), PIDD auto-processing protein unit 2 (MER063690), MUC1 self-cleaving mucin (MER074260), dystroglycan (MER054741), proprotein convertase 9 (MER022416), site-1 peptidase (MER001948), furin (MER000375), proprotein convertase 1 (MER000376), proprotein convertase 2 (MER000377), proprotein convertase 4 (MER028255), PACE4 proprotein convertase
- Oncomine (www.oncomine.org) is an online cancer gene expression database, and so when the agent of the invention is for treating cancer, the skilled person may search the Oncomine database to identify a particular protease cleavage site that will be appropriate for treating a given cancer type.
- Alternative databases include European Bioinformatic Institute (www.ebi.ac.uk) in particular (www.ebi.ac.uk/gxa).
- Protease databases include PMAP (www.proteolysis.org), ExPASy Peptide Cutter (ca.expasy.org/tools/peptide cutter) and PMAP.Cut DB (cutdb.burnham.org).
- peptides may be useful as linkers to join the T cell antigen to the targeting moiety as discussed below.
- Colo205 express barley any ADAM18/27 ADAM19 ADAM20 ADAM21/31 ADAM22 ADAM23 ADAM28 ADAM29 ADAM30 ADAM33 ADAMTS1 ADAMTS2 ADAMTS3 ADAMTS4 ADAMTS5/11 ADAMTS6 ADAMTS7 ADAMTS8 ADAMTS9 ADAMTS10 ADAMTS12 ADAMTS13 ADAMTS14 ADAMTS15 ADAMTS16 ADAMTS17 ADAMTS18 ADAMTS19 ADAMTS20
- proteolytic ADAMs a disintegrin and metalloproteinase
- mRNA or protein levels have been found to be upregulated relative to normal tissue (adapted from Nature Reviews Cancer 8, 932-941 (December 2008)
- the protease may be an esterase.
- cleavage sites include linkages which are labile under certain conditions in the vicinity of unwanted cells (eg tumour microenvironment).
- the cleavage site may comprise disulphide bonds, which can be reduced in the hypoxic tumour microenvironment, or may comprise pH sensitive moieties that break in acidic conditions. It will be understood, however, that the cleavage site must be selectively cleavable in the vicinity of the unwanted cells and so such linkages must be more labile and preferably only labile in the vicinity of unwanted cells compared to in the vicinity of wanted cells.
- the cleavage site may comprise nucleic acid (eg DNA or RNA) that is selectively cleavable in the vicinity of unwanted cells (eg by nucleases).
- nucleic acid eg DNA or RNA
- Other cleavage sites include phosphate, lipid or disulphide containing moieties that may be cleavable by appropriate enzymes.
- the T cell antigen is joined to the targeting moiety by a linker.
- linker we include the meaning of a chemical moiety that attaches the targeting moiety to the T cell antigen, and which comprises a cleavage site that is cleavable selectively in the vicinity of the unwanted cells as described herein.
- T cell antigen may either be bound covalently or non-covalently to the targeting moiety.
- the T cell antigen is covalently attached to the targeting moiety.
- the T cell antigen and targeting moiety are covalently attached by a linker.
- the T cell antigen (e.g. peptide) and targeting moiety may be conveniently linked by any of the conventional ways of cross-linking molecules, such as those generally described in O'Sullivan et al Anal. Biochem . (1979) 100, 100-108, and as described in Example 2.
- one of the T cell antigen e.g.
- peptide) or targeting moiety may be enriched with thiol groups and the other reacted with a bifunctional agent capable of reacting with those thiol groups, for example the N-hydroxysuccinimide ester of iodoacetic acid (NHIA) or N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), a heterobifunctional cross-linking agent which incorporates a disulphide bridge between the conjugated species.
- NHS iodoacetic acid
- SPDP N-succinimidyl-3-(2-pyridyldithio)propionate
- Amide and thioether bonds for example achieved with m-maleimidobenzoyl-N-hydroxysuccinimide ester, are generally more stable in vivo than disulphide bonds.
- bis-maleimide reagents allow the attachment of a thiol group (e.g. thiol group of a cysteine residue of an antibody) to another thiol-containing moiety (e.g. thiol group of a T cell antigen or a linker intermediate), in a sequential or concurrent fashion.
- thiol group e.g. thiol group of a cysteine residue of an antibody
- thiol group of a T cell antigen or a linker intermediate e.g. thiol group of a T cell antigen or a linker intermediate
- Other functional groups besides maleimide, which are reactive with a thiol group include iodoacetamide, bromoacetamide, vinyl pyridine, disulfide, pyridyl disulfide, isocyanate, and isothiocyanate.
- cross-linking agents include S-acetylthioglycolic acid N-hydroxysuccinimide ester (SATA) which is a thiolating reagent for primary amines which allows deprotection of the sulphydryl group under mild conditions (Julian et al (1983) Anal. Biochem. 132, 68), dimethylsuberimidate dihydrochloride and N,N′-o-phenylenedimaleimide.
- SATA S-acetylthioglycolic acid N-hydroxysuccinimide ester
- crosslinking agents include sulfosuccinimidyl 4-[N-maleimidomethyl]cyclohexane-1-carboxylate (Sulfo-SMCC), sulfosuccinimidyl 6-(3′-[2-pyridyldithio]-propionamido) hexanoate (Sulfo-LC-SPDP) and N-[ ⁇ -Maleimidopropionic acid]hydrazide, trifluoroacetic acid salt (BMPH).
- Sulfo-SMCC sulfosuccinimidyl 4-[N-maleimidomethyl]cyclohexane-1-carboxylate
- Sulfo-LC-SPDP sulfosuccinimidyl 6-(3′-[2-pyridyldithio]-propionamido) hexanoate
- BMPH trifluoroacetic acid salt
- the T cell antigen and targeting moiety do not need to be cross-linked directly to each other, but may be attached via one or more spacer moieties.
- the T cell antigen may be crosslinked to a chemical moiety which in turn is crosslinked to the targeting moiety.
- a spacer moiety may comprise a cleavage site that is cleavable selectively in the vicinity of the unwanted cells, as discussed below. It will be appreciated that the spacer moiety may serve to prevent steric hindrance and facilitate protease cleavage.
- Tables 6 and 7 provide examples of suitable T cell antigen peptides and how they may be incorporated into the agent of the invention.
- the T cell antigen peptide may be joined to a protease cleavage site via a first spacer moiety, and the protease cleavage site in turn joined to a linker moiety via a second spacer moiety.
- the linker may be used to attach the final peptide to the targeting moiety.
- Tables 6 and 7 also list the proteases that cleave the corresponding protease cleavage sites.
- peptides containing a T cell antigen and protease cleavage site that may be incorporated into the agent of the invention (e.g. by attachment to an appropriate targeting moiety such as an antibody) are listed in the table below.
- the T cell antigen peptide is attached to the targeting moiety, either directly or indirectly through a spacer moiety, at its N-terminus.
- FIG. 9B which lists three peptides that comprise a T cell epitope and a protease cleavage site.
- Peptides (i) and (ii) have the T cell epitope at the N-terminus so that the epitope is attached to the targeting moiety via a spacer moiety (comprising a protease cleavage site and a cysteine coupling residue) joined to the C-terminus of the epitope.
- peptide (iii) comprises the same T cell epitope but the epitope is attached to the targeting moiety via a spacer moiety (comprising a protease cleavage site and a cysteine coupling reside) joined to the N-terminus of the epitope.
- the N-terminus of the T-cell epitope is further away from the targeting moiety (configuration: N terminus-(T cell epitope)-C-terminus-Targeting moiety), whereas in peptide (iii), the C-terminus of the T-cell epitope is further away from the targeting moiety (configuration: C-terminus-(T cell epitope)-N-terminus-Targeting moiety).
- the configuration of peptide (iii) is the reverse of that of peptides (i) and (ii).
- the configuration of peptide (iii) is preferred.
- Table 7 provides examples of a suitable T cell antigen and how it may be incorporated into the agent of the invention such that the T cell antigen would be attached to the targeting moiety, either directly or indirectly through a spacer moiety at its N-terminus.
- the invention provides an agent for preventing or treating a condition characterised by the presence of unwanted cells, the agent comprising (i) a targeting moiety that is capable of targeting to the unwanted cells; (ii) a T cell antigen; and (iii) a cleavable site between the targeting moiety and T cell antigen, wherein the cleavable site can be selectively cleaved in the vicinity of the unwanted cells.
- the two components may be part of a fusion polypeptide that may be encoded by a nucleic acid molecule.
- the invention includes such a nucleic acid molecule and host cells containing them.
- an antibody targeting moiety may be genetically engineered to contain the T cell antigen using genetic engineering techniques well established in the art.
- the T cell antigen may be embedded within the polypeptide sequence of the targeting moiety, provided that it can be released so as to be capable of being presented on an unwanted cell to elicit a T cell response.
- the T cell antigen may reside within the polypeptide of the targeting moiety and be flanked by two cleavage sites which each may be selectively cleaved in the vicinity of the unwanted cell.
- the T cell antigen may reside at one terminus of the targeting moiety and be released by virtue of one cleavage site being cleaved.
- the T cell antigen and the targeting moiety are joined so that both portions retain their respective activities such that the agent may be targeted to an unwanted cell and the T cell antigen may be presented by the unwanted cell so as to elicit an immune response.
- the T cell antigen and targeting moiety portions are typically joined by a linker peptide which comprises a cleavage site that is cleavable selectively in the vicinity of the unwanted cells as described below.
- Suitable linker peptides are those that typically adopt a random coil conformation, for example the polypeptide may contain alanine or proline or a mixture of alanine plus proline residues.
- the linker contains between 2 and 100 amino acid residues, more preferably between 2 and 50 and still more preferably between 4 and 20.
- Polynucleotides which encode suitable targeting moieties are known in the art or can be readily designed from known sequences such as from sequences of proteins known to interact with surface markers expressed on unwanted cells or contained in nucleotide sequence databases such as the GenBank, EMBL and dbEST databases.
- T cell antigens are known in the art or can readily be designed from known sequences and made.
- polynucleotides which encode the agents used in the invention can readily be constructed using well known genetic engineering techniques.
- final peptide we mean the peptide that is attached to the targeting moiety, for example by crosslinking via a cysteine thiol group Epitope Spacer 1 Cleavage Spacer2 Linker
- Final Peptide Protease NLVPMVATV Q KWNKWALSR ASALASAL (SEQ C NLVPMVATVQKWNKWALSRASALASALC (SEQ ID No: (SEQ ID No: 282) (SEQ ID No: 283) 21) 281) NLVPMVATV Q HSSKLQL GGGSGGGGS C NLVPMVATVQHSSKLQLGGGSGGGGSC PSA (SEQ ID No: (SEQ ID No: (SEQ ID No: 284) (SEQ ID No: 285) 21) 266) NLVPMVATV Q GGGGF (SEQ GGGGFGGGGF C NLVPMVATVQGGGGFGGGGFGGGGFC Cathepsin B (SEQ ID No:
- final peptide we mean the peptide that is attached to the targeting moiety, for example by crosslinking via a cysteine thiol group Linker Spacer 1 Cleavage Spacer 2 Epitope
- Final Peptide Protease C SGGGGSGGGG CPGRVVGG A NLVPMVATV CSGGGGSGGGGCPGRVVGGANLVPMVATV uPa/tPA (SEQ ID No: (SEQ ID No: (SEQ ID No: (SEQ ID No: 297) 296) 254) 21) C SGGGGSGGGG GGR A NLVPMVATV CSGGGGSGGGGGGRANLVPMVATV (SEQ Plasmin/ (SEQ ID No: (SEQ ID No: ID No: 298) TMPRSS2 296) 21) C SGGGGSGGGG YLGRSYKV A NLVPMVATV CSGGGGSGGGGYLGRSYKVANLVPMVATV Cls
- nucleic acid is then expressed in a suitable host to produce an agent of the invention.
- nucleic acid encoding the agent of the invention may be used in accordance with known techniques, appropriately modified in view of the teachings contained herein, to construct an expression vector, which is then used to transform an appropriate host cell for the expression and production of the agent of the invention of the invention.
- nucleic acid encoding the agent of the invention may be joined to a wide variety of other nucleic acid sequences for introduction into an appropriate host.
- the companion nucleic acid will depend upon the nature of the host, the manner of the introduction of the nucleic acid into the host, and whether episomal maintenance or integration is desired, as is well known in the art.
- the T cell antigen and targeting moiety are non-covalently attached.
- immunological bindings or such binding as via biotin/avidin or streptavidin, respectively are preferred.
- the targeting moiety may be a bispecific antibody, one specificity of which is directed to an entity expressed by the unwanted cell and one specificity of which is directed to the T cell antigen or part thereof.
- the T cell antigen may contain further peptidic sequences which are recognised by the bispecific antibody.
- T cell antigen Another possibility involves coupling the targeting moiety, for example to streptavidin whilst the T cell antigen is coupled to biotin, and vice versa.
- Other means by which non-covalent interactions can be formed include leucine zipper sequences or affinity bonds.
- cleavage site that is cleavable selectively in the vicinity of the unwanted cells, such that the T cell antigen can be released from the targeting moiety.
- Amino acid residues described herein are generally in the natural “L” isomeric form. However, residues in the “D” isomeric form can be substituted for L-amino acid residues in certain situations, provided that the agent of the invention still retains its function, namely to prevent or treat a condition characterised by the presence of unwanted cells.
- the definition also includes, unless otherwise specifically indicated, chemically-modified amino acids, including amino acid analogues (such as penicillamine, 3-mercapto-D-valine), naturally-occurring non-proteogenic amino acids (such as norleucine), beta-amino acids, azapeptides, N-methylated amino acids and chemically-synthesised compounds that have properties known in the art to be characteristic of an amino acid.
- proteogenic indicates that the amino acid can be incorporated into a protein in a cell through well-known metabolic pathways.
- the definition also includes amino acids in which the functional side group has been chemically derivatised.
- derivatised molecules include, for example, those molecules in which free amino groups have been derivatised to form amine hydrochlorides, p-toluene sulfonyl groups, carbobenzoxy groups, t-butyloxycarbonyl groups, chloroacetyl groups or formyl groups.
- Free carboxyl groups may be derivatised to form salts, methyl and ethyl esters or other types of esters or hydrazides.
- Free hydroxyl groups may be derivatised to form O-acyl or O-alkyl derivatives.
- derivatives are those peptide portions that contain one or more naturally occurring amino acid derivatives of the twenty standard amino acids.
- the peptide portions of the agent of the invention can be peptide “mimetics”, i.e. peptidomimetics which mimic the structural features of peptides comprising or consisting of the amino acid sequence as described herein. Peptidomimetics can be even more advantageous in therapeutic use, in the resistance to degradation, in permeability or in possible oral administration.
- a primary goal in the design of peptide mimetics has been to reduce the susceptibility of mimetics to cleavage and inactivation by peptidases.
- one or more amide bonds have been replaced in an essentially isosteric manner by a variety of chemical functional groups.
- This stepwise approach has met with some success in that active analogues have been obtained. In some instances, these analogues have been shown to possess longer biological half-lives than their naturally-occurring counterparts.
- a variety of uncoded or modified amino acids such as D-amino acids and N-methyl amino acids have been used to modify mammalian peptides.
- a presumed bioactive conformation has been stabilised by a covalent modification, such as cyclization or by incorporation of ⁇ -lactam or other types of bridges (Veber et al, 1978) and Thorsett et al, 1983).
- a covalent modification such as cyclization or by incorporation of ⁇ -lactam or other types of bridges (Veber et al, 1978) and Thorsett et al, 1983).
- Rich (1986) has been to design peptide mimics through the application of the transition state analogue concept in enzyme inhibitor design.
- the secondary alcohol of statine mimics the tetrahedral transition state of the sessile amide bond of the pepsin substrate.
- Other approaches include the use of azapeptides and beta-amino acids.
- retro-inverso peptides also include the meaning of a peptide in which all of the L-amino acids are replaced with D-amino acids and the peptide bonds are reversed.
- the peptides are composed of D-amino acids assembled in the reverse order from that of the parent L-sequence.
- Retro-inverso peptides can be synthesised by methods known in the art, for example such as those described in Meziere et al (1997) J. Immunol. 159 3230-3237. This approach involves making pseudopeptides containing changes involving the backbone, and not the orientation of side chains which remain very similar to the parent peptide. Retro-inverse peptides are much more resistant to proteolysis.
- any of the targeting moiety, T cell antigen, cleavage site, spacer moieties and targeting moiety as described herein are peptides or polypeptides
- any one or more of those peptides or polypeptides may be substituted for a corresponding peptidomimetic that retains the respective activity of the parent peptide or polypeptide. This may help to confer protease resistance on the agent of the invention and thereby improve its stability.
- a T cell antigen is attached to a targeting moiety via one or more peptide spacer moieties, it may be desirable for one or more of those spacer moieties to be peptidomimetics, e.g. wherein one or more of the naturally occurring amino acids of the spacer moieties are replaced or modified, for example, to improve stability.
- stabilising groups include amido, acetyl, benzyl, phenyl, tosyl, alkoxycarbonyl, alkyl carbonyl, benzyloxycarbonyl and the like end group modifications. Additional modifications include using a “D” amino acid in place of a “L” amino acid at the termini, and amide rather than amino or carboxy termini or acetyl rather than amino termini, to inhibit exopeptidase activity.
- the agent of the invention may have a capping moiety, preferably a moiety that is less than 200 Da in molecular weight.
- Further capping moieties include a naftyl group or a polyethylene glycol group. It is appreciated that retro-inverso peptides are already relatively stable and so may not require additional capping moieties.
- the agent of the invention has a half-life in plasma of at least 24 hours at 37° C.
- agent of the invention may be modified so that it can be more easily detected, for example by biotinylating it or by incorporating any detectable label known in the art such as radiolabels, fluorescent labels or enzymatic labels.
- a particular preferred embodiment of the invention provides an agent for preventing or treating cancer, the agent comprising:
- a targeting moiety that is capable of targeting to the cancer
- T cell peptide can be released from the targeting moiety by selective cleavage in the vicinity of the cancer.
- the cancer may be any cancer such as breast cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, renal cancer, melanoma, lung cancer, prostate cancer, testicular cancer, thyroid cancer, brain cancer, oesophageal cancer, gastric cancer, pancreatic cancer, colorectal cancer, liver cancer, leukaemia, myeloma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, acute myeloid leukaemia, acute lymphoblastic leukaemia, chronic lymphoblastic leukaemia, lymphoproliferative disorder, myelodysplastic disorder, myeloproliferative disease and premalignant disease.
- cancer such as breast cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, renal cancer, melanoma, lung cancer, prostate cancer, testicular cancer, thyroid cancer, brain cancer, oesophageal cancer, gastric cancer, pancreatic cancer, colorectal cancer, liver cancer,
- agents of the invention may be used to redirect existing immune responses to kill particular unwanted cells in a specific manner. Since any unwanted cell may be targeted in this way, the agents of the invention offer significant therapeutic potential.
- a second aspect of the invention provides a method of preventing or treating a condition characterised by the presence of unwanted cells, the method comprising administering an agent according to the first aspect of the invention to a subject.
- the method may involve identifying a subject who has a condition or who is at risk of developing a condition characterised by unwanted cells (eg cancer), administering the agent according to the first aspect of the invention to the subject, and monitoring the levels of the unwanted cells in the subject either by conducting tests to determine the number of unwanted cells or by monitoring the clinical symptoms of the subject. Depending on the results of the monitoring step, it may be necessary to administer more of the agent.
- unwanted cells eg cancer
- the invention includes an agent according to the first aspect of the invention for use in preventing or treating a condition characterised by the presence of unwanted cells.
- the invention also includes the use of an agent according to the first aspect of the invention in the manufacture of a medicament for preventing or treating a condition characterised by the presence of unwanted cells.
- the unwanted cells are tumour cells and the condition is a tumour.
- preventing or treating a condition we include the meaning of reducing or alleviating symptoms in a patient (i.e. palliative use), preventing symptoms from worsening or progressing, treating the disorder (e.g. by inhibition or elimination of the causative agent), or prevention of the condition or disorder in a subject who is free therefrom.
- the agents of the invention lend themselves to personalised medicine in the clinic whereby the most appropriate agent to be administered to the patient is determined, and either selected or prepared in the clinic.
- any one of the following may be determined: (i) the MHC alleles of the subject, (ii) the cytotoxic T cell response of the subject to a T cell antigen and (iii) the expression profile of the unwanted cell with regards to a molecule which may be the target of the targeting moiety and/or an enzyme which is able to cleave the cleavage site in the agent of the invention.
- the MHC alleles of a subject can be assessed by serological assays at the antigen level or by using DNA assays at the genetic level. Determining whether a given antigen stimulates a specific cytotoxic T cell response in a subject can be done by contacting isolated peripheral mononuclear blood cells from the subject with the antigen and using standard assays for cell proliferation. Assessing the expression profile of the unwanted cell may be carried out on a biopsy sample using routine assays for measuring nucleic acid (e.g. DNA or RNA transcripts) or protein levels. For example, transcriptomic or proteomic techniques may be used. In this way, it will be possible to identify tailored targeting moieties that bind specifically to, for example, surface markers expressed by the unwanted cell. It may also be possible to identify appropriate protease cleavage sites that may be selectively cleaved in the vicinity of the unwanted cells.
- nucleic acid e.g. DNA or RNA transcripts
- proteomic or proteomic techniques may be used. In this way,
- the method of the second aspect of the invention may include the steps of (i) identifying a subject who has a condition, or who is at risk of developing a condition characterised by the presence of unwanted cells (eg cancer), (ii) taking a sample from the subject, (iii) analysing the sample to identify the optimum targeting moiety, T cell antigen and/or cleavage site for preventing or treating the condition in that subject, (iii) preparing the agent of the invention, (iv) administering the agent to the subject, and (v) monitoring the levels of unwanted cells in the subject either by conducting tests to determine the number of unwanted cells or by monitoring the clinical symptoms of the subject.
- unwanted cells eg cancer
- an apparatus may be used to select and optionally prepare the most appropriate agent to be used for a particular patient.
- the apparatus may perform an automated analysis of one or more samples from the subject, and based on this analysis select and optionally prepare a tailor-made agent for that subject.
- the apparatus may perform serological assays on the sample to determine a subject's MHC alleles and based on this test various peptides for their efficiency in eliciting cytotoxic T cell response, so as to identify the best T cell antigen for use in that patient.
- the apparatus may carry out an expression profile of unwanted cells from the subject (eg from a biopsy sample) so as to determine a suitable targeting moiety that will bind to the unwanted cell and/or determine a suitable cleavage site that will be selectively cleaved in the vicinity of the unwanted cell.
- the agent can contain a T cell antigen that is known to bind to patient's MHC molecules and elicit a strong T cell response, a targeting moiety that is known to bind selectively to surface markers expressed by the unwanted cell, and a protease cleavage site that allows the release of the T cell antigen in the vicinity of the unwanted cells.
- the subject is administered a further therapeutic agent in addition to the agent according to the first aspect of the invention.
- a further therapeutic agent known to be useful for combating that condition may be administered.
- a further anti-cancer agent eg anti-neoplastic chemotherapy
- the further therapeutic agent may be one that is known to have therapeutic application in allergic disease, inflammatory disease, regenerative medicine and neuroregenerative disease.
- the further therapeutic agent may be administered at the same time as the agent of the invention (i.e. simultaneous administration optionally in a co-formulation) or at a different time to the agent of the invention (i.e. sequential administration).
- the further therapeutic agent may be any one or more of a vaccine; an immuno stimulatory drug; an anti-cancer agent; an agent inhibiting an antibody response against the agent of the invention; and/or a protease inhibitor.
- the subject in order to boost the effector immune response against the particular T cell antigen used, it may be desirable to vaccinate the subject with the T cell antigen; and/or administer immunostimulating agents such as IL-2, IL-7, IFN ⁇ , GM-CSF, metformin, lenalidomide; and/or administer anti-immunoregulatory agents such as Ipilimumab; all of which may be considered as further therapeutic agents.
- immunostimulating agents such as IL-2, IL-7, IFN ⁇ , GM-CSF, metformin, lenalidomide
- anti-immunoregulatory agents such as Ipilimumab
- the subject may also be administered one or more agents that are known to inhibit the activity of B cells, such as any of Rituximab, cyclophosphamide, Syk inhibitors, an anti-BAFF antibody (eg Belimumab), an anti-CD22 antibody, an anti-CD20 antibody and an anti-CD19 antibody, all of which may be considered as further therapeutic agents.
- agents that are known to inhibit the activity of B cells such as any of Rituximab, cyclophosphamide, Syk inhibitors, an anti-BAFF antibody (eg Belimumab), an anti-CD22 antibody, an anti-CD20 antibody and an anti-CD19 antibody, all of which may be considered as further therapeutic agents.
- the inhibitor of B cells is administered to the subject prior to the agent of the invention, eg as a pre-treatment to ablate B cells.
- a particular protease inhibitor so as to improve the target selectivity of the agent of the invention.
- a targeting moiety is known to bind cells in both the heart and breast tissue, but only those in the breast are to be targeted, it may be desirable to administer an agent that selectively inhibits the protease responsible for releasing the T cell antigen, in the heart but not the breast.
- an agent is administered to inhibit a protease that is capable of releasing the T cell antigen but which protease resides in the vicinity (eg at or near the surface of) of wanted cells but not in the vicinity (eg at or near the surface of) of unwanted cells.
- a protease cleavage site of the agent of the invention is cleavable by multiple proteases, some of which reside in the vicinity of unwanted cells and some of which reside in the vicinity of wanted cells.
- targeting specificity may be improved by administering a protease inhibitor that inhibits a protease that resides in the vicinity of wanted cells but nevertheless is capable of cleaving the cleavage site and therefore releasing the T cell antigen from the agent of the invention.
- the effect of administering the inhibitor would be to ensure that the T cell antigen is preferentially released in the vicinity of the unwanted cells.
- a subject with cancer also has active rheumatoid arthritis where MMP2 and other proteases are active, and the one or more cleavage sites in the agent of the invention are cleavable by multiple proteases including MMP2, it may be beneficial to inhibit MMP2 to prevent cleavage of the agent at the arthritic joint but retain cleavage at the cancer site by another protease.
- the invention thus includes a composition comprising (i) an agent according to the first aspect of the invention and (ii) a further therapeutic agent, for use in preventing or treating a condition characterised by the presence of unwanted cells.
- a composition comprising (i) an agent according to the first aspect of the invention and (ii) a further therapeutic agent, for use in preventing or treating a condition characterised by the presence of unwanted cells.
- the agent of the invention and the further therapeutic agent may be administered simultaneously or sequentially
- the invention includes an agent according to the first aspect of the invention for use in preventing or treating a condition characterised by the presence of unwanted cells in a subject who is administered a further therapeutic agent.
- the invention includes a therapeutic agent for use in preventing or treating a condition characterised by the presence of unwanted cells in a subject who is administered an agent according to the first aspect of the invention.
- the invention includes a use of a composition comprising (i) an agent according to the first aspect of the invention and (ii) a further therapeutic agent, in the manufacture of a medicament for preventing or treating a condition characterised by the presence of unwanted cells.
- a composition comprising an agent according to the first aspect of the invention in the manufacture of a medicament for preventing or treating a condition characterised by the presence of unwanted cells in a subject who is administered a further therapeutic agent.
- the invention includes the use of a therapeutic agent in the manufacture of a medicament for preventing or treating a condition characterised by the presence of unwanted cells in a subject who is administered an agent according to the first aspect of the invention.
- the invention also provides a composition
- a composition comprising (i) an agent according to the first aspect of the invention and (ii) a further therapeutic agent suitable for preventing or treating the same condition characterised by the presence of unwanted cells.
- a further therapeutic agent suitable for preventing or treating the same condition characterised by the presence of unwanted cells.
- the therapeutic agent mentioned in the immediately preceding two paragraphs may be agents suitable for treating the same condition characterised by the presence of unwanted cells, as treatable by the agents of the invention.
- a third aspect of the invention provides an agent according to the first aspect of the invention for use in medicine.
- a fourth aspect of the invention a pharmaceutical composition
- a pharmaceutical composition comprising an agent according to the first aspect of the invention, and a pharmaceutically acceptable carrier, diluent or excipient.
- the agent of the invention Whilst it is possible for the agent of the invention to be administered alone, it is preferable to present it as a pharmaceutical formulation, together with one or more acceptable carriers.
- the carrier(s) must be “acceptable” in the sense of being compatible with the therapeutic agent and not deleterious to the recipients thereof.
- the carriers will be water or saline which will be sterile and pyrogen free.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient (agent for treating or preventing a condition characterised by unwanted cells) with the carrier which constitutes one or more accessory ingredients.
- the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
- Formulations in accordance with the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
- the active ingredient may also be presented as a bolus, electuary or paste.
- a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
- Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethylcellulose in varying proportions to provide desired release profile.
- Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouth-washes comprising the active ingredient in a suitable liquid carrier.
- Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
- the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
- Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
- the agent of the invention can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
- the agent may also be transdermally administered, for example, by the use of a skin patch.
- Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose or an appropriate fraction thereof, of an active ingredient.
- formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
- the amount of the agent which is administered to the individual is an amount effective to combat the particular individual's condition.
- the amount may be determined by the physician.
- the subject to be treated is a human.
- the subject may be an animal, for example a domesticated animal (for example a dog or cat), laboratory animal (for example laboratory rodent, for example mouse, rat or rabbit) or an animal important in agriculture (i.e. livestock), for example horses, cattle, sheep or goats.
- a domesticated animal for example a dog or cat
- laboratory animal for example laboratory rodent, for example mouse, rat or rabbit
- animal important in agriculture i.e. livestock
- horses, cattle, sheep or goats for example horses, cattle, sheep or goats.
- the invention provides a kit of parts for preventing or treating a condition characterised by the presence of unwanted cells, the kit comprising: (i) a targeting moiety that is capable of targeting to the unwanted cells and which is attached to a first binding partner, and (ii) a T cell antigen that is attached to a second binding partner which is capable of binding to the first binding partner, wherein the T cell antigen can be released from the second binding partner by selective cleavage of a cleavage site between the second binding partner and T cell antigen in the vicinity of the unwanted cells.
- kits of parts are for preventing or treating cancer.
- first and second binding partners we include the meaning of any two moieties which bind to each other selectively. Most preferably, the first and second binding partners only bind to each other and not to any other moieties. Non-covalent binding such as between biotin/avidin or streptavidin, or immunological bindings are preferred.
- the first binding partner may be biotin and the second binding partner may be avidin, and vice versa.
- the first binding partner may be an antigen and the second binding partner may be an antibody specific for that antigen, and vice versa.
- any pair of first and second binding partners that selectively bind to each other may be used, and suitable pairs will be known to the skilled person.
- the kit allows one to first administer the targeting moiety to the subject, and establish the correct localisation of the targeting moiety in the subject (for example by the targeting moiety being detectably labelled (eg radiolabelled)) before administering the T cell antigen.
- the T cell antigen is then targeted to the unwanted cells by virtue of the second binding partner binding to the first binding partner. Once in the vicinity of the unwanted cells, the T cell antigen will be released from the second binding partner by selective cleavage of a cleavage site between the second binding partner and T cell antigen, allowing it to be presented on the surface of the unwanted cells so as to re-direct an existing immune response to the unwanted cells.
- the invention further provides a method of preventing or treating a condition characterised by the presence of unwanted cells, the method comprising administering (i) a targeting moiety that is capable of targeting to the unwanted cells and which is attached to a first binding partner, and (ii) a T cell antigen that is attached to a second binding partner which is capable of binding to the first binding partner, wherein the T cell antigen can be released from the second binding partner by selective cleavage of a cleavage site between the second binding partner and T cell antigen in the vicinity of the unwanted cells, to the subject.
- the targeting moiety is administered before the T cell antigen, for example to allow to correct localisation of the targeting moiety at the unwanted cells to be established.
- the targeting moiety may be administered at the same time as the T cell antigen.
- the invention provides a targeting moiety that is capable of targeting to unwanted cells and which is attached to a first binding partner, and a T cell antigen that is attached to a second binding partner which is capable of binding to the first binding partner, wherein the T cell antigen can be released from the second binding partner by selective cleavage of a cleavage site between the second binding partner and T cell antigen in the vicinity of the unwanted cells, for use in preventing or treating a condition characterised by unwanted cells in a subject.
- the targeting moiety is administered before the T cell antigen, for example to allow to correct localisation of the targeting moiety at the unwanted cells to be established.
- the targeting moiety may be administered at the same time as the T cell antigen. It is appreciated that the targeting moiety and T cell antigen may be attached to each other by binding of the first and second binding partners.
- a further kit of parts provided by the invention comprises (i) a targeting moiety that is capable of targeting to unwanted cells, (ii) a T cell antigen, and (iii) one or more means or reagents to assess one or more of a subject's (a) MHC alleles, (b) cytotoxic T cell response to a T cell antigen and (c) expression profile of an unwanted cell in the subject.
- kits of parts may be useful in tailoring a particular agent as defined in the first aspect of the invention for a given patient. Suitable means or reagents that can be used to assess a subject's (a) MHC alleles, (b) cytotoxic T cell response to a T cell antigen and (c) expression profile of an unwanted cell in the subject, are well known and widely available in the art.
- the kit of parts comprises the agent of the first aspect of the invention and the kit may be used to determine whether that agent is suitable for a particular patient.
- the invention also provides a molecule comprising (i) a T cell antigen and (ii) a cleavage site; wherein the cleavage site contains a linking moiety to allow the molecule to be attached to a targeting moiety which targeting moiety is capable of targeting to unwanted cells, and wherein the cleavage site can be selectively cleaved in the vicinity of the unwanted cells.
- the molecule may represent the part of the agent of the first aspect of the invention, without the targeting moiety.
- preferences for the T cell antigen, the cleavage site, how the cleavage site is attached to the targeting moiety (e.g. via a linker moiety comprising a thiol group such a cysteine residue), the targeting moiety and unwanted cells include all of those defined above with respect to the first aspect of the invention.
- the molecule comprises those final peptides listed in Table 6 above, wherein the ‘epitope’ listed in Table 6 corresponds to the T cell antigen of the molecule, and wherein the ‘cleavage sequence’ listed in Table 6 corresponds to the cleavage site.
- the molecule may comprise or consist of any of the peptides:
- NLVPMVATVQKWNKWALSRASALASALC NLVPMVATVQKWNKWALSRASALASALC
- SEQ ID No: 285 NLVPMVATVQHSSKLQLGGGSGGGGSC
- SEQ ID No: 287 NLVPMVATVQGGGGFGGGGFGGGGFC
- SEQ ID No: 288) NLVPMVATVQKQSRKFVPGGGSGGGGSC
- SEQ ID No: 292 NLVPMVATVQGPQGIASQGGGSGGGGSC
- SEQ ID No: 293 NLVPMVATVQPQGIAGQGGGSGGGGSC
- SEQ ID No: 295) NLVPMVATVQVLKVLKVLKVLKGGGSGGGGSC.
- the molecule comprises those final peptides listed in Table 7 above, wherein the ‘epitope’ listed in Table 7 corresponds to the T cell antigen of the molecule, and wherein the ‘cleavage site’ listed in Table 7 corresponds to the cleavage site.
- the molecule may comprise or consist of any of the peptides:
- the molecule comprises or consists of any of the following peptides:
- the targeting moiety described herein is Cetuximab
- the T cell antigen comprises NLVPMVATV (SEQ ID No: 21)
- the cleavage site comprises a MMP14 cleavage sequence.
- the targeting moiety described herein is Rituximab
- the T cell antigen comprises DYSNTHSTRYV (SEQ ID No: 55)
- the cleavage site comprises a MMP2 cleavage sequence.
- the targeting moiety described herein is Rituximab
- the T cell antigen is TPRVTGGGAM (SEQ ID No: 31)
- the cleavage site comprises a MMP2 cleavage sequence.
- the targeting moiety described herein is hP67.6 (Gemtuzumab parent antibody), the T cell antigen is TPRVTGGGAM (SEQ ID No: 31) and the cleavage site comprises a MMP2 cleavage sequence.
- the targeting moiety described herein is Cetuximab
- the T cell antigen comprises NLVPMVATV (SEQ ID No: 21)
- the cleavage site comprises any of the following cleavage sequences: a uPa/tPa cleavage sequence (CPGR-VVGG) (SEQ ID No: 254), a Plasmin/TMPRSS2 cleavage sequence (GGR-X) (SEQ ID No: 256), a C1s cleavage (YLGR-SYKV) (SEQ ID No: 257), a MASP2 cleavage sequence (SLGR-KIQI) (SEQ ID No: 259), a thrombin cleavage sequence (LVPRGS) (SEQ ID No: 260), a trypsin cleavage sequence (XXXR-X) (SEQ ID No: 261), an elastase 2 cleavage sequence (AAPV-X) (SEQ ID No: 262),
- MDA.MB.231 cells often used as a model for breast cancer, were transduced with the MMP14 gene to ensure expression of the MMP14 protein within the cell.
- T cells cultured together with cells stained using Cetuximab alone and cetuximab conjugated with the mismatched HLA-peptide There was very little IFN- ⁇ release from T cells cultured together with cells stained using Cetuximab alone and cetuximab conjugated with the mismatched HLA-peptide.
- T cells cultured with cells stained using cetuximab conjugated with the correct peptide but lacking the MMP14 cleavage site also produced very little IFN- ⁇ whereas T cells cultured with the cells stained using cetuximab conjugated with the correct peptide containing the MMP14 cleavage site produced a large amount of IFN- ⁇ .
- B-lymphoblastoid cells B-LCL
- an agent comprising Rituximab conjugated to a cytomegalovirus HLA Class-II restricted peptide DYSNTHSTRYV (SEQ ID No: 55) with and without a cleavage site.
- CD4 + T cells resulted in the generation of a T cell response when the B-LCL cells were contacted with the agent that contained the cleavage site.
- T cells were cultured with Rituximab conjugated with the HLA-mismatched peptide containing the protease cleavage site there was no IFN- ⁇ produced. The results are shown in FIG. 2 .
- FIG. 3 A similar example showing stimulation of CD4 + T cells by Rituximab TPRVTGGGAM conjugate is shown in FIG. 3 .
- An agent comprising Cetuximab that is attached to a peptide T cell antigen such as NLVPMVATV (SEQ ID No: 21), derived from a cytomegalovirus, via a linker comprising a PRSA-KELR (SEQ ID No: 321) protease cleavage site (cleavable by Matrix metalloproteinase 14 (MMP14)) is prepared.
- the agent is formulated with a pharmaceutically acceptable excipient and administered to patient with an epithelial malignancy such as breast cancer.
- the agent, Cetuximab is targeted to breast cancer cells and upon binding comes into contact with MMP14.
- the cleavage of the protease cleavage site releases the T cell antigen, NLVPMVATV (SEQ ID No: 21), which subsequently binds to the HLA-A*0201 molecules on the surface of the breast cancer cell.
- NLVPMVATV SEQ ID No: 21
- the breast cancer cells expressing the T cell antigen is targeted by the host immune system for cytolysis by the effector CD8 T cells.
- B-Cell Lymphoma eg Chronic Lymphocytic Leukaemia
- An agent comprising Rituximab that is attached to a HLA class-II peptide T cell antigen such as DYSNTHSTRYV (SEQ ID No: 55), derived from a cytomegalovirus, via a linker comprising a TIPV-SLRS (SEQ ID No: 317) protease cleavage site (cleavable by Matrix metalloproteinase 2 (MMP2)) is prepared.
- the agent is formulated with a pharmaceutically acceptable excipient and administered to patient with B cell lymphoma (eg chronic lymphocytic leukaemia).
- B cell lymphoma eg chronic lymphocytic leukaemia.
- the agent, Rituximab is targeted to B cells and upon binding comes into contact with a protease.
- the subsequent cleavage of the protease cleavage site releases the T cell antigen, DYSNTHSTRYV (SEQ ID No: 55), which subsequently binds to the HLA-DR*0107 molecules on the surface of the B cell.
- the B cells expressing the T cell antigen would then be targeted by the host immune system for cytolysis by the effector CD4 T cells.
- An agent comprising Cetuximab that is attached to a peptide T cell antigen derived from a cytomegalovirus via a linker comprising a CPGR-VVGG (SEQ ID No: 254) protease cleavage site (cleavable by uPA) is prepared.
- the agent is formulated with a pharmaceutically acceptable excipient and administered to a bowel cancer patient.
- B Cell Lymphoma eg Chronic Lymphocytic Leukaemia (CLL)
- An agent comprising Rituximab that is attached to a peptide T cell antigen derived from a cytomegalovirus via a linker comprising a PQG-IAGQ (SEQ ID No: 269) protease cleavage site (cleavable by MMP2) is prepared.
- the agent is formulated with a pharmaceutically acceptable excipient and administered to a B cell lymphoma (eg CLL) cancer patient.
- B-lymphoblastoid cells B-LCL
- an agent comprising Rituximab conjugated to a cytomegalovirus peptide TPRVTGGGAM (SEQ ID No: 31) with and without a cleavage site.
- TPRVTGGGAM cytomegalovirus peptide
- T cells cultured together with cells stained using Rituximab conjugated with the mismatched HLA-peptide with or without the protease cleavage site (1 & 2).
- T cells cultured with cells stained using Rituximab conjugated with the correct peptide but lacking the protease cleavage site also produced very little IFN- ⁇ (4) whereas T cells cultured with the cells stained using Rituximab conjugated with the correct peptide containing the protease cleavage site (3) produced a large amount of IFN- ⁇ .
- B Cell Lymphoma eg Chronic Lymphocytic Leukaemia
- An agent comprising Rituximab that is attached to a HLA class-I peptide T cell antigen such as TPRVTGGGAM (SEQ ID No: 31), derived from a cytomegalovirus, via a linker comprising a TIPV-SLRS (SEQ ID No: 317) protease cleavage site (cleavable by Matrix metalloproteinase 2 (MMP2)) is prepared.
- the agent is formulated with a pharmaceutically acceptable excipient and administered to patients with B cell lymphoma (eg chronic lymphocytic leukaemia).
- B cell lymphoma eg chronic lymphocytic leukaemia.
- the agent, Rituximab is targeted to B cells and upon binding comes into contact with a protease.
- TPRVTGGGAM T cell antigen
- HLA-A2+ tumor cell lines THP-1 (acute monocytic leukemia cell line); A498 (renal cell carcinoma); MDA-MB-231 and MCF-7 (breast cell adenocarcinomas); NCI-H522 (non-small cell lung carcinoma); Ovcar-3 (ovarian adenocarcinoma); Colo205 and HCT-116 (colorectal carcinoma)
- THP-1 acute monocytic leukemia cell line
- A498 renal cell carcinoma
- MDA-MB-231 and MCF-7 breast cell adenocarcinomas
- NCI-H522 non-small cell lung carcinoma
- Ovcar-3 ovarian adenocarcinoma
- Colo205 and HCT-116 colonrectal carcinoma
- Antibody-peptide epitope conjugates were generated, through covalently linking T cell epitope peptides with clinically available antibodies Cetuximab and Rituximab. Neither APEC in solution nor plate-bound were able to activate cognate T cells. Healthy CD20+ B cells bound Ritixumab-APEC (RPEC) but were unable to activate T cells in vitro. However, CD20+ lymphoma cell lines were able to be efficiently targeted by T cells when bound by RPEC in vitro through proteolytic release of bound peptide demonstrating differential tumor targeting ( FIG. 5 ).
- FIGS. 7B and 7C demonstrate successful targeting of colorectal adenocarcinoma cell lines and pancreatic carcinoma cell lines using an anti-Muc1 antibody peptide conjugate.
- FIG. 7D demonstrates successful targeting of T cells using a protein that contains a viral peptide sequence as part of its polypeptide chain.
- a single chain fragment V (scFv) antibody-like construct was prepared, encoding a protease recognition domain and T cell epitope, and shown to efficiently target MDA-MB-231 cells in vitro.
- FIG. 8A shows that the conjugates according to the invention may be used to selectively target cancer cells. Following labelling of lymphoblastoid cells or healthy B cells with Rituximab conjugated with viral peptide, there is no recognition of healthy B cells whereas there is recognition of lymphoblastoid cells only in the presence of the viral peptide that the T cells are specific for.
- FIG. 8B demonstrates plasma and serum stability of conjugates according to the invention.
- FIG. 10A demonstrates the mechanism of action of the Cetuximab-peptide complex occurring at the cell surface and not by way of internalisation of the whole complex.
- chemical fixation of target cells By chemical fixation of target cells, internalisation of the complex is inhibited and a positive IFN- ⁇ response using fixed cells would demonstrate external processing of the APEC.
- the results show that target cells chemically fixed demonstrate a similar ability to induce IFN- ⁇ production by T cells when they are incubated with Cetuximab-NLVPMVATV-Protease Cleavage as that seen when target cells have not been chemically fixed.
- chemically fixed target cells cannot induce an IFN- ⁇ response when labelled with an irrelevant APEC (Cetuximab-VLEETSVML-Protease Cleavage) similar to that seen in untreated target cells.
- FIG. 10B demonstrates the ability to use a peptide as a targeting moiety in place of an antibody.
- Peptides which directly bind to either EGF receptor or Her2/neu receptor were synthesised containing a protease cleavage sequence and the viral epitope named receptor peptides (EGF-NLVPMVATV (NLVPMVATVAIPVSLRSAAAYCRDYDYDGRYFDCY) (SEQ ID No: 314) Ponde et al (2011) Bioorg Med Chem Lett, 21 or Her2-NLVPMVATV (NLVPMVATVAIPVSLRSAAAFCDGFYACYMDV) (SEQ ID No: 311) Park et al (2000) Nat Biotech 18).
- Target cells labelled with either peptide were able to induce an IFN- ⁇ response from viral-specific CD8+ T cells similar to that seen when target cells were pulsed with exogenous viral peptide. When either receptor peptide is removed, the target cells were not recognised by the T cells.
- FIG. 13 shows that antibody peptide epitope complexes (APEC) formed of anti-EGFR Cetuximab and peptides were able to re-target antigen specific T cells to target these malignant cell lines, but only when the peptide contained a protease cleavage site.
- APEC antibody peptide epitope complexes
- FIG. 14 shows that antigen specific T cells are at the tumour site and that other antibodies may be used in the approach (eg anti-MUC1 antibody SM3).
- the figure also demonstrates selective targeting of malignant cells compared to healthy cells.
- the anti-CD20 Rituximab APEC efficiently targets malignant lymphoma cells in vitro but spares healthy B cells derived from peripheral blood ( FIG. 14C ).
- the figure also shows the applicability toward MHC Class-II restricted peptides using CD4+ cytotoxic T cells ( FIG. 14D ), and that the APEC approach does not require the antigen processing capacity of target cells ( FIG. 14E ) suggesting that peptide cleavage is occurring at the cell membrane.
- a Xenograft model used NOG mice (NOD Rag2 ⁇ / ⁇ ⁇ c ⁇ / ⁇ ) (M. Ito et al., Blood 100, 3175 (2002)).
- Tumour cell lines were grown using standard laboratory tissue culture techniques and injected subcutaneously into the mice.
- Human T cells were cultured using standard techniques from healthy laboratory donors.
- T cells, antibody, or APEC is injected into the intraperitoneal cavity.
- Mice were injected with luciferin and growth and metastatic dissemination of the cells monitored using IVIS Spectrum (Caliper Lifesciences). Quantitation of outgrowth kinetics is determined and metastasis quantified by measuring luminescent signal from each organ at the experimental endpoint.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Virology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Genetics & Genomics (AREA)
- Zoology (AREA)
- Oncology (AREA)
- Cell Biology (AREA)
- Biochemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Biophysics (AREA)
- Biomedical Technology (AREA)
- Pulmonology (AREA)
- Hematology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Diabetes (AREA)
- Wood Science & Technology (AREA)
- Endocrinology (AREA)
- General Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Heart & Thoracic Surgery (AREA)
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1104514.3 | 2011-03-17 | ||
GBGB1104514.3A GB201104514D0 (en) | 2011-03-17 | 2011-03-17 | Re-directed immunotherapy |
GB1203434.4 | 2012-02-28 | ||
GBGB1203434.4A GB201203434D0 (en) | 2012-02-28 | 2012-02-28 | Re-directed immunotherapy |
PCT/GB2012/050577 WO2012123755A1 (en) | 2011-03-17 | 2012-03-15 | Re-directed immunotherapy |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2012/050577 A-371-Of-International WO2012123755A1 (en) | 2011-03-17 | 2012-03-15 | Re-directed immunotherapy |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/660,137 Continuation US9358282B2 (en) | 2011-03-17 | 2015-03-17 | Re-directed immunotherapy |
Publications (2)
Publication Number | Publication Date |
---|---|
US20140004081A1 US20140004081A1 (en) | 2014-01-02 |
US9402916B2 true US9402916B2 (en) | 2016-08-02 |
Family
ID=46026856
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/005,452 Expired - Fee Related US9402916B2 (en) | 2011-03-17 | 2012-03-15 | Re-directed immunotherapy |
US14/660,137 Active US9358282B2 (en) | 2011-03-17 | 2015-03-17 | Re-directed immunotherapy |
US14/972,059 Expired - Fee Related US10287321B2 (en) | 2011-03-17 | 2015-12-16 | Re-directed immunotherapy |
US16/366,240 Active 2032-06-06 US11236131B2 (en) | 2011-03-17 | 2019-03-27 | Re-directed immunotherapy |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/660,137 Active US9358282B2 (en) | 2011-03-17 | 2015-03-17 | Re-directed immunotherapy |
US14/972,059 Expired - Fee Related US10287321B2 (en) | 2011-03-17 | 2015-12-16 | Re-directed immunotherapy |
US16/366,240 Active 2032-06-06 US11236131B2 (en) | 2011-03-17 | 2019-03-27 | Re-directed immunotherapy |
Country Status (8)
Country | Link |
---|---|
US (4) | US9402916B2 (zh) |
EP (2) | EP3138581B1 (zh) |
JP (2) | JP6130307B2 (zh) |
CN (2) | CN110038135B (zh) |
AU (2) | AU2012228100B2 (zh) |
CA (1) | CA2830349C (zh) |
DK (2) | DK3138581T3 (zh) |
WO (1) | WO2012123755A1 (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20160106862A1 (en) * | 2011-03-17 | 2016-04-21 | The University Of Birmingham | Re-Directed Immunotherapy |
WO2020162696A1 (ko) * | 2019-02-08 | 2020-08-13 | 주식회사 굳티셀 | 암 치료를 위한 t 세포의 활성화 방법 |
US11759444B2 (en) | 2015-07-31 | 2023-09-19 | The Johns Hopkins University | Methods for cancer and immunotherapy using prodrugs of glutamine analogs |
Families Citing this family (62)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SG11201404711WA (en) | 2012-02-16 | 2014-09-26 | Vlp Therapeutics Llc | Virus like particle composition |
GB201203442D0 (en) | 2012-02-28 | 2012-04-11 | Univ Birmingham | Immunotherapeutic molecules and uses |
WO2014028069A1 (en) * | 2012-08-17 | 2014-02-20 | Flextronics Ap, Llc | Epg aggregation from multiple sources |
GB201216649D0 (en) * | 2012-09-18 | 2012-10-31 | Univ Birmingham | Agents and methods |
EP3677310A1 (en) | 2012-10-08 | 2020-07-08 | St. Jude Children's Research Hospital | Therapies based on control of regulatory t cell stability and function via a neuropilin-1:semaphorin axis |
US9066928B1 (en) * | 2012-12-04 | 2015-06-30 | University Of Kentucky Research Foundation | Method, composition, and kit useful for treatment of alzheimer's disease |
CN113699114A (zh) | 2013-02-26 | 2021-11-26 | 纪念斯隆-凯特琳癌症中心 | 用于免疫疗法的组合物和方法 |
CN105339389B (zh) | 2013-05-02 | 2021-04-27 | 安奈普泰斯生物有限公司 | 针对程序性死亡-1(pd-1)的抗体 |
GB201311487D0 (en) * | 2013-06-27 | 2013-08-14 | Alligator Bioscience Ab | Bispecific molecules |
AU2014300503B2 (en) | 2013-06-28 | 2018-11-22 | Auckland Uniservices Limited | Amino acid and peptide conjugates and conjugation process |
GB201312133D0 (en) * | 2013-07-05 | 2013-08-21 | Univ Birmingham | Immunotherapy |
TWI676636B (zh) | 2013-07-12 | 2019-11-11 | Vlp醫療股份有限公司 | 包含pd-1抗原或pd-1配體抗原的類病毒粒子 |
WO2015138638A1 (en) | 2014-03-11 | 2015-09-17 | Theraly Pharmaceuticals, Inc. | Long acting trail receptor agonists for treatment of autoimmune diseases |
US9394365B1 (en) | 2014-03-12 | 2016-07-19 | Yeda Research And Development Co., Ltd | Reducing systemic regulatory T cell levels or activity for treatment of alzheimer's disease |
KR20230097209A (ko) | 2014-03-12 | 2023-06-30 | 예다 리서치 앤드 디벨럽먼트 캄파니 리미티드 | Cns의 질환 및 손상을 치료하기 위한 전신적 조절 t 세포 수준 또는 활성의 감소 |
US10519237B2 (en) | 2014-03-12 | 2019-12-31 | Yeda Research And Development Co. Ltd | Reducing systemic regulatory T cell levels or activity for treatment of disease and injury of the CNS |
US10618963B2 (en) | 2014-03-12 | 2020-04-14 | Yeda Research And Development Co. Ltd | Reducing systemic regulatory T cell levels or activity for treatment of disease and injury of the CNS |
WO2015199618A1 (en) * | 2014-06-24 | 2015-12-30 | National University Of Singapore | Epstein-barr virus lmp2 specific antibody and uses thereof |
EP3164417A1 (en) | 2014-07-01 | 2017-05-10 | Pfizer Inc. | Bispecific heterodimeric diabodies and uses thereof |
BR112017001242A2 (pt) | 2014-07-21 | 2017-12-05 | Novartis Ag | tratamento de câncer usando um receptor antigênico quimérico a cd33 |
US9546206B2 (en) | 2014-08-08 | 2017-01-17 | The Board Of Trustees Of The Leland Stanford Junior University | High affinity PD-1 agents and methods of use |
TWI720946B (zh) | 2014-08-08 | 2021-03-11 | 美商Vlp醫療股份有限公司 | 包含改質套膜蛋白質e3之類病毒粒子 |
US10385101B2 (en) | 2014-08-08 | 2019-08-20 | Vlp Therapeutics, Llc | Virus like particle comprising modified envelope protein E3 |
AU2015313650B2 (en) | 2014-09-11 | 2021-07-08 | Vlp Therapeutics, Inc. | Flavivirus virus like particle |
DK3186192T3 (en) * | 2014-09-30 | 2018-04-23 | Thena Biotech S R L | FUSION PROTEIN, NANOPARTICLE CONSISTS OF A MULTIPLE OF MONOMERS OF THE FUSION PROTEIN AND APPLICATIONS THEREOF |
CN107001444B (zh) * | 2014-12-17 | 2020-11-27 | 中国科学院广州生物医药与健康研究院 | 识别eb病毒短肽的t细胞受体 |
CN107250103A (zh) | 2014-12-23 | 2017-10-13 | 玛格丽特·安妮·布林布尔 | 氨基酸缀合物和肽缀合物以及其用途 |
JP2018508481A (ja) | 2015-02-02 | 2018-03-29 | ザ ユニバーシティ オブ バーミンガム | 複数のt細胞エピトープを有する標的化部分ペプチドエピトープ複合体 |
AU2016302940B2 (en) | 2015-07-31 | 2021-02-04 | The Johns Hopkins University | Prodrugs of glutamine analogs |
CN108348492B (zh) * | 2015-07-31 | 2021-09-28 | 约翰霍普金斯大学 | 使用谷氨酰胺类似物的用于癌症和免疫疗法的方法 |
EP3370755B1 (en) | 2015-11-06 | 2021-09-29 | Regents of the University of Minnesota | Activation of resident memory t cells for cancer immunotherapy |
PT3377103T (pt) | 2015-11-19 | 2021-05-26 | Revitope Ltd | Complementação de fragmento de anticorpo funcional para um sistema de dois componentes para exterminação redirecionada de células indesejadas |
CN108601819B (zh) | 2015-12-17 | 2022-03-15 | 约翰霍普金斯大学 | 用死亡受体激动剂改善系统性硬化症 |
CN105418766A (zh) * | 2015-12-22 | 2016-03-23 | 深圳市北科生物科技有限公司 | 一种用于免疫治疗的eb病毒lmp2a串联表位肽及其应用 |
WO2017147368A1 (en) * | 2016-02-24 | 2017-08-31 | Oncomed Pharmaceuticals, Inc. | Redirecting immune responses |
SG11201807036QA (en) | 2016-02-26 | 2018-09-27 | Auckland Uniservices Ltd | Amino acid and peptide conjugates and conjugation process |
JP7281795B2 (ja) | 2016-04-07 | 2023-05-26 | ザ・ジョンズ・ホプキンス・ユニバーシティー | 膵炎および疼痛をデス受容体アゴニストで処置するための組成物および方法 |
AU2017354070A1 (en) | 2016-11-01 | 2019-05-16 | Anaptysbio, Inc. | Antibodies directed against programmed death- 1 (PD-1) |
BR112019008265A2 (pt) | 2016-11-28 | 2019-07-09 | Chugai Pharmaceutical Co Ltd | molécula de ligação ao ligante cuja atividade de li-gação ao ligante é ajustável |
CN110177875B (zh) | 2016-11-28 | 2023-11-28 | 中外制药株式会社 | 包含抗原结合结构域和运送部分的多肽 |
MX2019008207A (es) | 2017-01-09 | 2019-12-11 | Tesaro Inc | Métodos para tratar el cáncer con anticuerpos anti-pd-1. |
WO2018200766A1 (en) | 2017-04-26 | 2018-11-01 | Mayo Foundation For Medical Education And Research | Methods and materials for treating cancer |
US11858974B2 (en) * | 2017-05-22 | 2024-01-02 | Resq Biotech | Macrocyclic modulators of disease associated protein misfolding and aggregation |
BR112019027488A2 (pt) | 2017-06-23 | 2020-07-07 | Pathovax Llc | partículas semelhantes a vírus quiméricas e usos destas como redirecionadores de respostas imunológicas antígeno-específicos |
US11969463B2 (en) | 2017-08-10 | 2024-04-30 | Good T Cells, Inc. | Method for activating T cells for cancer treatment |
KR20200047687A (ko) | 2017-09-08 | 2020-05-07 | 매버릭 테라퓨틱스, 인크. | 제약된 조건적으로 활성화된 결합 단백질 |
BR112020010450A2 (pt) | 2017-11-28 | 2020-11-24 | Chugai Seiyaku Kabushiki Kaisha | polipeptídeo que inclui domínio de ligação a antígeno e seção transportadora |
AU2018392884B2 (en) * | 2017-12-20 | 2021-11-11 | Glaxosmithkline Biologicals Sa | Epstein-Barr Virus antigen constructs |
CN110151987B (zh) * | 2018-02-11 | 2023-10-13 | 汕头大学医学院 | 对称IgG及其组合物在制备治疗及预防肿瘤的药物中的用途 |
WO2019220209A1 (en) * | 2018-05-18 | 2019-11-21 | The Council Of The Queensland Institute Of Medical Research | Adoptive t-cell therapy for cmv infection and cmv-associated diseases |
EP3816182A4 (en) * | 2018-05-30 | 2022-07-13 | Chugai Seiyaku Kabushiki Kaisha | LIGAND BINDING MOLECULE WITH SINGLE DOMAIN ANTIBODY |
JP7414736B2 (ja) | 2018-05-30 | 2024-01-16 | 中外製薬株式会社 | アグリカン結合ドメインおよび運搬部分を含むポリペプチド |
EP3806962A1 (en) | 2018-06-13 | 2021-04-21 | Novartis AG | Bcma chimeric antigen receptors and uses thereof |
US11560408B2 (en) | 2018-12-27 | 2023-01-24 | Verimmune Inc. | Conjugated virus-like particles and uses thereof as anti-tumor immune redirectors |
EP3725370A1 (en) | 2019-04-19 | 2020-10-21 | ImmunoBrain Checkpoint, Inc. | Modified anti-pd-l1 antibodies and methods and uses for treating a neurodegenerative disease |
WO2020219425A1 (en) * | 2019-04-25 | 2020-10-29 | Seattle Children's Hospital (dba Seattle Children's Research Institute) | Combinatorial car t cell and hematopoeitic stem cell genetic engineering for specific immunotherapy of myeloid leukemias |
WO2021013932A1 (en) * | 2019-07-23 | 2021-01-28 | Deutsches Krebsforschungszentrum | Polypeptides for treatment of aml |
US20230076637A1 (en) | 2020-02-06 | 2023-03-09 | Ajou University Industry-Academic Cooperation Foundation | Fusion antibody for presenting antigen-derived t cell antigen epitope or peptide containing same on cell surface, and composition comprising same |
US11767353B2 (en) | 2020-06-05 | 2023-09-26 | Theraly Fibrosis, Inc. | Trail compositions with reduced immunogenicity |
JP2023552040A (ja) | 2020-10-19 | 2023-12-14 | ヴェリミューン インコーポレイテッド | ウイルスにインスパイアされた組成物及びがんの治療のために同じものを使用して、既存の免疫応答をリダイレクトする方法 |
CN117222667A (zh) * | 2021-03-16 | 2023-12-12 | Jn生物科学有限责任公司 | 用于治疗免疫失调的双功能分子 |
CN114874329A (zh) * | 2022-05-19 | 2022-08-09 | 江苏大学 | 一种补体活化C1s酶荧光检测试剂盒及检测方法与应用 |
Citations (46)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1216649A (en) | 1968-11-29 | 1970-12-23 | Atlantic Richfield Co | Purification of epoxides |
EP0659438A1 (en) | 1993-12-23 | 1995-06-28 | Boehringer Mannheim Gmbh | Conjugates consisting of peptidic T cell antigens and cell binding groups, and their use for therapy |
WO1996034892A1 (en) | 1995-05-03 | 1996-11-07 | Bioenhancements Ltd. | Bispecific antibodies in which the binding capability is reversibly inhibited by a photocleavable moiety |
US5585089A (en) | 1988-12-28 | 1996-12-17 | Protein Design Labs, Inc. | Humanized immunoglobulins |
WO1997023237A1 (en) | 1995-12-22 | 1997-07-03 | Immunomedics, Inc. | Use of immunoconjugates to enhance the efficacy of multi-stage cascade boosting vaccines |
WO1998010651A1 (en) | 1996-09-12 | 1998-03-19 | Merck & Co., Inc. | Conjugates useful in the treatment of prostate cancer |
US5739116A (en) | 1994-06-03 | 1998-04-14 | American Cyanamid Company | Enediyne derivatives useful for the synthesis of conjugates of methyltrithio antitumor agents |
WO1998018493A2 (en) | 1996-10-30 | 1998-05-07 | Merck & Co., Inc. | Conjugates useful in the treatment of prostate cancer |
WO1998024478A2 (en) | 1996-11-30 | 1998-06-11 | Enzacta R & D Limited | Tumour therapy |
WO1998041641A1 (en) | 1997-03-20 | 1998-09-24 | The Government Of The United States As Represented By The Secretary Of The Department Of Health And Human Services | Recombinant antibodies and immunoconjugates targeted to cd-22 bearing cells and tumors |
WO1999002175A1 (en) | 1997-07-10 | 1999-01-21 | Merck & Co., Inc. | Conjugates useful in the treatment of prostate cancer |
WO2000006605A2 (en) | 1998-07-28 | 2000-02-10 | Micromet Ag | Heterominibodies |
WO2002044197A2 (en) | 2000-12-01 | 2002-06-06 | Fish Eleanor N | Cytokine receptor binding peptides |
WO2003027135A2 (en) | 2001-09-26 | 2003-04-03 | The Government Of The United States, As Represented By The Secretary Of Health And Human Services | Mutated anti-cd22 antibodies with increased affinity to cd22-expressing leukemia cells |
US20040001853A1 (en) | 2002-06-20 | 2004-01-01 | Rajan George | Chimeric antigens for eliciting an immune response |
WO2004069876A2 (en) | 2003-02-06 | 2004-08-19 | Micromet Ag | Trimeric polypeptide construct to induce an enduring t cell response |
US20050037001A1 (en) | 2001-11-30 | 2005-02-17 | Germeraad Wilfred Thomas Vincent | APC targeting conjugate, an antigen-presenting cell contacted with such conjugate, their medical use, and methods of production |
US6896881B1 (en) * | 1999-09-24 | 2005-05-24 | Mayo Foundation For Medical Education And Research | Therapeutic methods and compositions using viruses of the recombinant paramyxoviridae family |
WO2005052004A2 (en) | 2003-11-28 | 2005-06-09 | Micromet Ag | Compositions comprising polypeptides |
WO2005061547A2 (en) | 2003-12-22 | 2005-07-07 | Micromet Ag | Bispecific antibodies |
WO2005083431A2 (en) | 2004-02-25 | 2005-09-09 | Bloenhancements Limited | Binding agents |
US20060045881A1 (en) * | 2004-08-26 | 2006-03-02 | Board Of Regents, The University Of Texas System | Anti-cancer vaccines |
US20060088522A1 (en) | 2004-09-10 | 2006-04-27 | Wyeth | Humanized anti-5T4 antibodies and anti-5T4/calicheamicin conjugates |
EP1664270A1 (en) | 2003-08-08 | 2006-06-07 | ViRexx Medical Corp. | Chimeric antigens for breaking host tolerance to foreign antigens |
US7151164B2 (en) | 2002-02-14 | 2006-12-19 | Immunomedics, Inc. | Anti-CD20 antibodies and fusion proteins thereof and methods of use |
WO2007057922A1 (en) | 2005-11-18 | 2007-05-24 | Dabur Pharma Limited | Targeted fusion proteins for cancer therapy |
WO2007107764A1 (en) | 2006-03-21 | 2007-09-27 | Biotransformations Limited | Reversibly inhibited antibodies for immune cell stimulation |
WO2007136778A2 (en) * | 2006-05-19 | 2007-11-29 | Teva Pharmaceutical Industries, Ltd. | Fusion proteins, uses thereof and processes for producing same |
WO2008019366A2 (en) | 2006-08-07 | 2008-02-14 | Ludwig Institute For Cancer Research | Methods and compositions for increased priming of t-cells through cross-presentation of exogenous antigens |
WO2008052322A1 (en) | 2006-10-30 | 2008-05-08 | Viventia Biotech Inc. | Immunotoxγn fusions comprising an antibody fragment and a plant toxin linked by protease cleavable linkers |
WO2008063113A1 (en) | 2006-11-20 | 2008-05-29 | Cepep Iii Ab | Cell -penetrating peptides and constructs containing them consisting 15-25 amino acids of tumor supressor protein p14arf or p19arf |
EP1948802A1 (en) | 2005-10-13 | 2008-07-30 | ViRexx Medical Corp. | Chimeric antigen containing hepatitis c virus polypeptide and fc fragment for eliciting an immune response |
WO2008097866A2 (en) | 2007-02-02 | 2008-08-14 | Baylor Research Institute | Vaccines based on targeting antigen to dcir expressed an antigen-presenting cells |
WO2009025846A2 (en) | 2007-08-22 | 2009-02-26 | The Regents Of The University Of California | Activatable binding polypeptides and methods of identification and use thereof |
WO2009024771A2 (en) | 2007-08-17 | 2009-02-26 | Biotransformations Limited | Materials and methods for treating cancers which express folate receptors |
US20090214543A1 (en) * | 2005-02-16 | 2009-08-27 | University Of Zurich | Methods for treating cancer using an immuno-toxin comprising an exotoxin a moiety having a furin cleavage site replaced with a cancer associated protease site cleaved by mmp-2 or mmp-9 |
US7659241B2 (en) | 2002-07-31 | 2010-02-09 | Seattle Genetics, Inc. | Drug conjugates and their use for treating cancer, an autoimmune disease or an infectious disease |
WO2010037837A2 (en) | 2008-10-01 | 2010-04-08 | Micromet Ag | Bispecific single chain antibodies with specificity for high molecular weight target antigens |
WO2010081173A2 (en) | 2009-01-12 | 2010-07-15 | Cytomx Therapeutics, Llc | Modified antibody compositions, methods of making and using thereof |
US20100189727A1 (en) * | 2008-12-08 | 2010-07-29 | Tegopharm Corporation | Masking Ligands For Reversible Inhibition Of Multivalent Compounds |
US20100291082A1 (en) | 2009-03-10 | 2010-11-18 | Baylor Research Institute | Antigen presenting cell targeted anti-viral vaccines |
US20110008840A1 (en) | 2002-11-07 | 2011-01-13 | Immunogen, Inc. | Anti-cd33 antibodies and methods for treatment of acute myeloid leukemia using the same |
US7884184B2 (en) | 2007-01-30 | 2011-02-08 | Epivax, Inc. | Regulatory T cell epitopes, compositions and uses thereof |
WO2011056721A2 (en) | 2009-11-05 | 2011-05-12 | Center For Molecular Medicine And Immunology | Immunoconjugates comprising poxvirus-derived peptides and antibodies against antigen-presenting cells for subunit-based poxvirus vaccines |
WO2012123755A1 (en) | 2011-03-17 | 2012-09-20 | The University Of Birmingham | Re-directed immunotherapy |
WO2013139789A1 (en) | 2012-03-19 | 2013-09-26 | Deutsches Krebsforschungszentrum | B-cell receptor complex binding proteins containing t-cell epitopes |
Family Cites Families (74)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9014932D0 (en) | 1990-07-05 | 1990-08-22 | Celltech Ltd | Recombinant dna product and method |
EP0699237B1 (en) | 1994-03-17 | 2003-02-19 | MERCK PATENT GmbH | Anti-egfr single-chain fvs and anti-egfr antibodies |
US5610281A (en) | 1994-05-03 | 1997-03-11 | Brigham & Women's Hospital, Inc. | Antibodies for modulating heterotypic E-cadherin interactions with human T lymphocytes |
US5698679A (en) | 1994-09-19 | 1997-12-16 | National Jewish Center For Immunology And Respiratory Medicine | Product and process for targeting an immune response |
US20080286228A1 (en) * | 1995-10-20 | 2008-11-20 | Tarantolo Stefano R | Compositions and methods for enhancing immune responses mediated by antigen-presenting cells |
US6541212B2 (en) | 1997-03-10 | 2003-04-01 | The Regents Of The University Of California | Methods for detecting prostate stem cell antigen protein |
DE122007000021I1 (de) | 1997-04-07 | 2007-05-24 | Genentech Inc | Anti-vefg Antibodies |
JP4566290B2 (ja) | 1997-04-30 | 2010-10-20 | ツインストランド・ホールディングス・インコーポレイテッド | 癌、ウイルスまたは寄生虫感染を治療するためのリシン様毒素変異体 |
JP2002507397A (ja) | 1998-03-13 | 2002-03-12 | エピミューン,インコーポレイティド | Hla結合ペプチド及びその使用 |
JP2003502273A (ja) | 1998-09-01 | 2003-01-21 | ザ ガバメント オブ ザ ユナイテッド ステイツ オブ アメリカ, リプリゼンテッド バイ ザ セクレタリー オブ ザ デパートメント オブ ヘルス アンド ヒューマン サービシーズ | 正常な前立腺、精巣、および子宮ならびに新生物性の前立腺、精巣、および子宮に発現されたx連鎖gage様遺伝子であるpage−4、ならびにその使用 |
TWI318983B (en) | 2000-05-02 | 2010-01-01 | Uab Research Foundation | An antibody selective for a tumor necrosis factor-related apoptosis-inducing ligand receptor and uses thereof |
US6458552B1 (en) | 2000-06-06 | 2002-10-01 | Ortho-Mcneil Pharmaceutical, Inc. | Metalloprotease peptide substrates and methods |
US20060062786A1 (en) | 2000-11-08 | 2006-03-23 | Human Genome Sciences, Inc. | Antibodies that immunospecifically bind to TRAIL receptors |
PE20020801A1 (es) | 2001-01-05 | 2002-09-06 | Pfizer | Anticuerpos contra el receptor del factor de crecimiento similar a insulina |
GEP20074091B (en) | 2001-04-26 | 2007-04-25 | Biogen Idec Inc | Cripto blocking antibodies and uses thereof |
JP4309662B2 (ja) | 2001-05-03 | 2009-08-05 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング | 腫瘍特異的組換え抗体およびその使用 |
US7115717B2 (en) | 2001-05-18 | 2006-10-03 | Kirin Beer Kabushiki Kaisha | Anti-TRAIL-R antibodies |
AU2002351208A1 (en) | 2001-12-03 | 2003-06-17 | Abgenix, Inc. | Antibodies against carbonic anhydrase IX (CA IX) tumor antigen |
AU2003224604B2 (en) | 2002-01-28 | 2007-06-14 | Medarex, Inc. | Human monoclonal antibodies to prostate specific membrane antigen (PSMA) |
US8877901B2 (en) | 2002-12-13 | 2014-11-04 | Immunomedics, Inc. | Camptothecin-binding moiety conjugates |
CA2485548A1 (en) | 2002-05-10 | 2004-02-19 | Purdue Research Foundation | Epha2 agonistic monoclonal antibodies and methods of use thereof |
ATE525398T1 (de) | 2002-05-10 | 2011-10-15 | Medimmune Inc | Epha2 monoklonale antikörper und deren anwendungsverfahren |
AU2003265866A1 (en) | 2002-09-03 | 2004-03-29 | Vit Lauermann | Targeted release |
CN101658672B (zh) | 2002-10-08 | 2017-09-26 | 免疫医疗公司 | 用iii类抗cea单克隆抗体和治疗剂进行联合治疗 |
US7595379B2 (en) | 2003-05-30 | 2009-09-29 | Agensys, Inc. | Antibodies and related molecules that bind to PSCA proteins |
IL156495A0 (en) | 2003-06-17 | 2004-01-04 | Prochon Biotech Ltd | Use of fgfr3 antagonists for treating t cell mediated diseases |
FR2858235B1 (fr) | 2003-07-31 | 2006-02-17 | Lab Francais Du Fractionnement | Utilisation d'anticorps optimises en adcc pour traiter les patients faibles repondeurs |
HN2004000285A (es) | 2003-08-04 | 2006-04-27 | Pfizer Prod Inc | ANTICUERPOS DIRIGIDOS A c-MET |
EP1699492A2 (en) | 2003-12-31 | 2006-09-13 | Sanofi Pasteur Inc. | Targeted immunogens |
US7273608B2 (en) | 2004-03-11 | 2007-09-25 | City Of Hope | Humanized anti-CEA T84.66 antibody and uses thereof |
CN102698267B (zh) | 2004-08-24 | 2017-07-21 | 中外制药株式会社 | 使用抗磷脂酰肌醇蛋白聚糖‑3抗体的辅助疗法 |
BRPI0518279A2 (pt) | 2004-10-26 | 2008-11-11 | Chugai Pharmaceutical Co Ltd | anticorpo antiglipicam 3 tendo cadeia de aÇécar modificada |
WO2006048877A2 (en) | 2004-11-04 | 2006-05-11 | Fibron Limited | Treatment of b-cell malignancies with fgfr3 inhibitors |
CN101137673B (zh) | 2005-01-05 | 2013-12-04 | 比奥根艾迪克Ma公司 | Cripto结合分子 |
US8029783B2 (en) | 2005-02-02 | 2011-10-04 | Genentech, Inc. | DR5 antibodies and articles of manufacture containing same |
BRPI0607796A2 (pt) | 2005-02-18 | 2009-06-13 | Medarex Inc | composto ou um sal farmaceuticamente aceitável do mesmo, processo para preparação e uso do mesmo, e, composição farmacêutica |
UA92504C2 (en) | 2005-10-12 | 2010-11-10 | Эли Лилли Энд Компани | Anti-myostatin monoclonal antibody |
EP1790358A1 (en) | 2005-11-23 | 2007-05-30 | Université de Reims Champagne-Ardennes | Protein constructs designed for targeting and lysis of cells |
WO2007065027A2 (en) | 2005-12-02 | 2007-06-07 | Dana Farber Cancer Institute | Carbonic anhydrase ix (g250) antibodies and methods of use thereof |
ES2385054T3 (es) | 2005-12-13 | 2012-07-17 | Medimmune Limited | Proteínas de unión específicas para factores de crecimiento de tipo insulina y usos de las mismas |
EP1988896A4 (en) | 2006-02-22 | 2011-07-27 | 3M Innovative Properties Co | CONJUGATES TO MODIFY IMMUNE REACTIONS |
EP1993608A1 (en) * | 2006-03-10 | 2008-11-26 | Diatos | Anticancer drugs conjugated to antibody via an enzyme cleavable linker |
RU2008142833A (ru) | 2006-03-30 | 2010-05-10 | Новартис АГ (CH) | КОМПОЗИЦИИ И СПОСОБЫ ПРИМЕНЕНИЯ АНТИТЕЛ К c-Met |
WO2008011157A2 (en) * | 2006-07-20 | 2008-01-24 | The General Hospital Corporation | Methods, compositions, and kits for the selective activation of protoxins through combinatorial targeting |
JP2010508043A (ja) | 2006-10-31 | 2010-03-18 | イミュノジェン・インコーポレーテッド | 抗体産生を改善するための方法 |
WO2008115641A2 (en) | 2007-02-15 | 2008-09-25 | Yale University | Modular nanoparticles for adaptable vaccines |
AU2008235566B2 (en) | 2007-04-04 | 2013-06-06 | Alfasigma S.p.A | Anti-EpCAM antibody and uses thereof |
US7723485B2 (en) | 2007-05-08 | 2010-05-25 | Genentech, Inc. | Cysteine engineered anti-MUC16 antibodies and antibody drug conjugates |
WO2008143666A2 (en) | 2007-05-17 | 2008-11-27 | Genentech, Inc. | Crystal structures of neuropilin fragments and neuropilin-antibody complexes |
WO2008144029A1 (en) | 2007-05-14 | 2008-11-27 | The University Of Chicago | Antibody-light fusion products for cancer therapeutics |
RU2525133C2 (ru) | 2007-08-30 | 2014-08-10 | Дайити Санкио Компани, Лимитед | Антитело к epha2 |
EP2197491A4 (en) | 2007-09-04 | 2011-01-12 | Univ California | HIGHAFFINE ANTI-PROSTATE STEM CELL ANTIGEN (PSCA) ANTIBODIES TO CANCER AND TO THE DETECTION OF CANCER |
US8039597B2 (en) | 2007-09-07 | 2011-10-18 | Agensys, Inc. | Antibodies and related molecules that bind to 24P4C12 proteins |
PE20091163A1 (es) | 2007-11-01 | 2009-08-09 | Wyeth Corp | Anticuerpos para gdf8 |
DK2215121T3 (en) | 2007-11-26 | 2016-05-02 | Bayer Ip Gmbh | ANTI-mesothelin ANTIBODIES AND USES THEREOF |
TWI472339B (zh) | 2008-01-30 | 2015-02-11 | Genentech Inc | 包含結合至her2結構域ii之抗體及其酸性變異體的組合物 |
RU2011103199A (ru) | 2008-06-30 | 2012-08-10 | Онкотерапи Сайенс, Инк. (Jp) | Антитела против cdh3, меченные радиоизотопной меткой, и их применение |
SG171812A1 (en) | 2008-12-04 | 2011-07-28 | Abbott Lab | Dual variable domain immunoglobulins and uses thereof |
KR20120034591A (ko) | 2009-03-06 | 2012-04-12 | 어젠시스 인코포레이티드 | 24p4c12 단백질에 결합하는 항체 약물 컨쥬게이트(adc) |
GB0909904D0 (en) | 2009-06-09 | 2009-07-22 | Affitech As | Product |
DK2542590T4 (da) | 2010-03-05 | 2020-07-13 | Univ Johns Hopkins | Sammensætninger og fremgangsmåde til målrettede immunomodulatoriske antistof-fer og fusionproteiner |
BR112012022917A2 (pt) | 2010-03-11 | 2017-01-10 | Pfizer | anticorpos com ligação a antígeno dependente de ph |
PT2552959T (pt) | 2010-03-26 | 2017-04-21 | Memorial Sloan Kettering Cancer Center | Anticorpos para muc16 e métodos de utilização dos mesmos |
US9149542B2 (en) | 2010-07-01 | 2015-10-06 | Aeon Medix Inc. | Microvesicles derived from cell protoplast and use thereof |
WO2012031609A1 (en) | 2010-09-07 | 2012-03-15 | Johannes Kepler Universität Linz | Biodegradable, water soluble and ph responsive poly(organo)phosphazenes |
GB201019118D0 (en) | 2010-11-11 | 2010-12-29 | King S College | Conjugates and their uses in molecular imaging |
WO2013054320A1 (en) | 2011-10-11 | 2013-04-18 | Tel Hashomer Medical Research Infrastructure And Services Ltd. | Antibodies to carcinoembryonic antigen-related cell adhesion molecule (ceacam) |
WO2013082366A1 (en) | 2011-12-01 | 2013-06-06 | The Brigham And Women's Hospital, Inc. | Anti-ceacam1 recombinant antibodies for cancer therapy |
GB201203442D0 (en) * | 2012-02-28 | 2012-04-11 | Univ Birmingham | Immunotherapeutic molecules and uses |
WO2014043523A1 (en) * | 2012-09-14 | 2014-03-20 | The Johns Hopkins University | Compositions and methods for rendering tumor cells susceptible to cd8+ t cell-mediated killing |
GB201216649D0 (en) * | 2012-09-18 | 2012-10-31 | Univ Birmingham | Agents and methods |
GB201312133D0 (en) * | 2013-07-05 | 2013-08-21 | Univ Birmingham | Immunotherapy |
KR102272213B1 (ko) * | 2014-07-08 | 2021-07-01 | 삼성전자주식회사 | 표적화 부위, 절단 부위, 및 세포막 투과 부위를 포함하는 융합 단백질 및 그의 용도 |
CA2975439A1 (en) * | 2015-02-18 | 2016-08-25 | F.Hoffmann-La Roche Ag | Immunoconjugates for specific induction of t cell cytotoxicity against a target cell |
-
2012
- 2012-03-15 CA CA2830349A patent/CA2830349C/en active Active
- 2012-03-15 JP JP2013558513A patent/JP6130307B2/ja not_active Expired - Fee Related
- 2012-03-15 CN CN201811559481.4A patent/CN110038135B/zh not_active Expired - Fee Related
- 2012-03-15 WO PCT/GB2012/050577 patent/WO2012123755A1/en active Application Filing
- 2012-03-15 EP EP16191609.3A patent/EP3138581B1/en active Active
- 2012-03-15 DK DK16191609.3T patent/DK3138581T3/en active
- 2012-03-15 AU AU2012228100A patent/AU2012228100B2/en active Active
- 2012-03-15 EP EP12718715.1A patent/EP2686020B1/en active Active
- 2012-03-15 US US14/005,452 patent/US9402916B2/en not_active Expired - Fee Related
- 2012-03-15 DK DK12718715.1T patent/DK2686020T3/en active
- 2012-03-15 CN CN201280024084.1A patent/CN103561771B/zh active Active
-
2015
- 2015-03-17 US US14/660,137 patent/US9358282B2/en active Active
- 2015-12-16 US US14/972,059 patent/US10287321B2/en not_active Expired - Fee Related
-
2016
- 2016-11-16 AU AU2016259343A patent/AU2016259343B2/en active Active
-
2017
- 2017-04-12 JP JP2017078724A patent/JP6449933B2/ja active Active
-
2019
- 2019-03-27 US US16/366,240 patent/US11236131B2/en active Active
Patent Citations (51)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1216649A (en) | 1968-11-29 | 1970-12-23 | Atlantic Richfield Co | Purification of epoxides |
US5585089A (en) | 1988-12-28 | 1996-12-17 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5693762A (en) | 1988-12-28 | 1997-12-02 | Protein Design Labs, Inc. | Humanized immunoglobulins |
EP0659438A1 (en) | 1993-12-23 | 1995-06-28 | Boehringer Mannheim Gmbh | Conjugates consisting of peptidic T cell antigens and cell binding groups, and their use for therapy |
WO1995017212A1 (en) | 1993-12-23 | 1995-06-29 | Boehringer Mannheim Gmbh | Conjugates consisting of peptidic t cell antigens and cell binding partners and their use for therapy |
US5739116A (en) | 1994-06-03 | 1998-04-14 | American Cyanamid Company | Enediyne derivatives useful for the synthesis of conjugates of methyltrithio antitumor agents |
US5773001A (en) | 1994-06-03 | 1998-06-30 | American Cyanamid Company | Conjugates of methyltrithio antitumor agents and intermediates for their synthesis |
US5767285A (en) | 1994-06-03 | 1998-06-16 | American Cyanamid Company | Linkers useful for the synthesis of conjugates of methyltrithio antitumor agents |
WO1996034892A1 (en) | 1995-05-03 | 1996-11-07 | Bioenhancements Ltd. | Bispecific antibodies in which the binding capability is reversibly inhibited by a photocleavable moiety |
WO1997023237A1 (en) | 1995-12-22 | 1997-07-03 | Immunomedics, Inc. | Use of immunoconjugates to enhance the efficacy of multi-stage cascade boosting vaccines |
WO1998010651A1 (en) | 1996-09-12 | 1998-03-19 | Merck & Co., Inc. | Conjugates useful in the treatment of prostate cancer |
WO1998018493A2 (en) | 1996-10-30 | 1998-05-07 | Merck & Co., Inc. | Conjugates useful in the treatment of prostate cancer |
WO1998024478A2 (en) | 1996-11-30 | 1998-06-11 | Enzacta R & D Limited | Tumour therapy |
WO1998041641A1 (en) | 1997-03-20 | 1998-09-24 | The Government Of The United States As Represented By The Secretary Of The Department Of Health And Human Services | Recombinant antibodies and immunoconjugates targeted to cd-22 bearing cells and tumors |
WO1999002175A1 (en) | 1997-07-10 | 1999-01-21 | Merck & Co., Inc. | Conjugates useful in the treatment of prostate cancer |
WO2000006605A2 (en) | 1998-07-28 | 2000-02-10 | Micromet Ag | Heterominibodies |
US6896881B1 (en) * | 1999-09-24 | 2005-05-24 | Mayo Foundation For Medical Education And Research | Therapeutic methods and compositions using viruses of the recombinant paramyxoviridae family |
WO2002044197A2 (en) | 2000-12-01 | 2002-06-06 | Fish Eleanor N | Cytokine receptor binding peptides |
WO2003027135A2 (en) | 2001-09-26 | 2003-04-03 | The Government Of The United States, As Represented By The Secretary Of Health And Human Services | Mutated anti-cd22 antibodies with increased affinity to cd22-expressing leukemia cells |
US20050037001A1 (en) | 2001-11-30 | 2005-02-17 | Germeraad Wilfred Thomas Vincent | APC targeting conjugate, an antigen-presenting cell contacted with such conjugate, their medical use, and methods of production |
US7151164B2 (en) | 2002-02-14 | 2006-12-19 | Immunomedics, Inc. | Anti-CD20 antibodies and fusion proteins thereof and methods of use |
US20040001853A1 (en) | 2002-06-20 | 2004-01-01 | Rajan George | Chimeric antigens for eliciting an immune response |
US7659241B2 (en) | 2002-07-31 | 2010-02-09 | Seattle Genetics, Inc. | Drug conjugates and their use for treating cancer, an autoimmune disease or an infectious disease |
US20110008840A1 (en) | 2002-11-07 | 2011-01-13 | Immunogen, Inc. | Anti-cd33 antibodies and methods for treatment of acute myeloid leukemia using the same |
WO2004069876A2 (en) | 2003-02-06 | 2004-08-19 | Micromet Ag | Trimeric polypeptide construct to induce an enduring t cell response |
WO2005087813A1 (en) | 2003-02-13 | 2005-09-22 | Virexx Research, Inc. | Chimeric antigens comprising an fc-fragment for eliciting an immune response |
EP1664270A1 (en) | 2003-08-08 | 2006-06-07 | ViRexx Medical Corp. | Chimeric antigens for breaking host tolerance to foreign antigens |
WO2005052004A2 (en) | 2003-11-28 | 2005-06-09 | Micromet Ag | Compositions comprising polypeptides |
WO2005061547A2 (en) | 2003-12-22 | 2005-07-07 | Micromet Ag | Bispecific antibodies |
WO2005083431A2 (en) | 2004-02-25 | 2005-09-09 | Bloenhancements Limited | Binding agents |
US20060045881A1 (en) * | 2004-08-26 | 2006-03-02 | Board Of Regents, The University Of Texas System | Anti-cancer vaccines |
US20060088522A1 (en) | 2004-09-10 | 2006-04-27 | Wyeth | Humanized anti-5T4 antibodies and anti-5T4/calicheamicin conjugates |
US20090214543A1 (en) * | 2005-02-16 | 2009-08-27 | University Of Zurich | Methods for treating cancer using an immuno-toxin comprising an exotoxin a moiety having a furin cleavage site replaced with a cancer associated protease site cleaved by mmp-2 or mmp-9 |
EP1948802A1 (en) | 2005-10-13 | 2008-07-30 | ViRexx Medical Corp. | Chimeric antigen containing hepatitis c virus polypeptide and fc fragment for eliciting an immune response |
WO2007057922A1 (en) | 2005-11-18 | 2007-05-24 | Dabur Pharma Limited | Targeted fusion proteins for cancer therapy |
WO2007107764A1 (en) | 2006-03-21 | 2007-09-27 | Biotransformations Limited | Reversibly inhibited antibodies for immune cell stimulation |
WO2007136778A2 (en) * | 2006-05-19 | 2007-11-29 | Teva Pharmaceutical Industries, Ltd. | Fusion proteins, uses thereof and processes for producing same |
WO2008019366A2 (en) | 2006-08-07 | 2008-02-14 | Ludwig Institute For Cancer Research | Methods and compositions for increased priming of t-cells through cross-presentation of exogenous antigens |
WO2008052322A1 (en) | 2006-10-30 | 2008-05-08 | Viventia Biotech Inc. | Immunotoxγn fusions comprising an antibody fragment and a plant toxin linked by protease cleavable linkers |
WO2008063113A1 (en) | 2006-11-20 | 2008-05-29 | Cepep Iii Ab | Cell -penetrating peptides and constructs containing them consisting 15-25 amino acids of tumor supressor protein p14arf or p19arf |
US7884184B2 (en) | 2007-01-30 | 2011-02-08 | Epivax, Inc. | Regulatory T cell epitopes, compositions and uses thereof |
WO2008097866A2 (en) | 2007-02-02 | 2008-08-14 | Baylor Research Institute | Vaccines based on targeting antigen to dcir expressed an antigen-presenting cells |
WO2009024771A2 (en) | 2007-08-17 | 2009-02-26 | Biotransformations Limited | Materials and methods for treating cancers which express folate receptors |
WO2009025846A2 (en) | 2007-08-22 | 2009-02-26 | The Regents Of The University Of California | Activatable binding polypeptides and methods of identification and use thereof |
WO2010037837A2 (en) | 2008-10-01 | 2010-04-08 | Micromet Ag | Bispecific single chain antibodies with specificity for high molecular weight target antigens |
US20100189727A1 (en) * | 2008-12-08 | 2010-07-29 | Tegopharm Corporation | Masking Ligands For Reversible Inhibition Of Multivalent Compounds |
WO2010081173A2 (en) | 2009-01-12 | 2010-07-15 | Cytomx Therapeutics, Llc | Modified antibody compositions, methods of making and using thereof |
US20100291082A1 (en) | 2009-03-10 | 2010-11-18 | Baylor Research Institute | Antigen presenting cell targeted anti-viral vaccines |
WO2011056721A2 (en) | 2009-11-05 | 2011-05-12 | Center For Molecular Medicine And Immunology | Immunoconjugates comprising poxvirus-derived peptides and antibodies against antigen-presenting cells for subunit-based poxvirus vaccines |
WO2012123755A1 (en) | 2011-03-17 | 2012-09-20 | The University Of Birmingham | Re-directed immunotherapy |
WO2013139789A1 (en) | 2012-03-19 | 2013-09-26 | Deutsches Krebsforschungszentrum | B-cell receptor complex binding proteins containing t-cell epitopes |
Non-Patent Citations (150)
Title |
---|
Adis R&D Profile: Brentuximab Vedotin, Drugs R D 11(1):85-95 (2011). |
Akiyama et al., "Characterization of cytomegalovirus pp65-HLA-A24 peptide-specific CTL lines from metastatic melanoma patients", Oncology Reports 22: pp. 185-191 (Mar. 3, 2009). |
Alderson RF, et al. CAT-8015: a second-generation pseudomonas exotoxin A-based immunotherapy targeting CD22-expressing hematologic malignancies. Clin Cancer Res. 15(3):832-9. Feb. 1, 2009. |
Alegretti AP, et al. Expression of CD55 and CD59 on peripheral blood cells from systemic lupus erythematosus (SLE) patients. Cell Immunol. 265(2):127-32. 2010; Epub Aug. 2, 2010. |
Alexander, J., et al., "Linear PADRE T Helper Epitope and Carbohydrate B Cell Epitope Conjugates Induce Specific High Titer IgG Antibody Responses," J. Immunol. 164:1625-1633 (2000). |
Alisa, A, et al. "Human CD4(+) T cells recognize an epitope within alpha-fetoprotein sequence and develop into TGF-beta-producing CD4(+) T cells," J Immunol. Apr. 1, 2008;180(7):5109-17. |
Appay V. The physiological role of cytotoxic CD4(+) T-cells: the holy grail? Clin Exp Immunol. 138(1):10-13. 2004. |
Arai K, et al., "Preventing effect of anti-ICAM-1 and anti-LFA-1 monoclonal antibodies on murine islet allograft rejection," International Journal of Pancreatology, Aug. 1999, vol. 26, Issue 1, pp. 23-31. |
Ariel O, et al. Signal transduction by CD58: the transmembrane isoform transmits signals outside lipid rafts independently of the GPI-anchored isoform. Cell Signal. 21(7):1100-8. Jul. 2009. Epub Mar. 5, 2009. |
Baeuerle P.A., et al. "BiTE: Teaching antibodies to engage T-cells for cancer therapy." Curr Opin Mol Therapeutics. 11 (1):22-30. (Feb. 1, 2009). |
Baeuerle, P.A. and Reinhardt, C., "Bispecific T-Cell Engaging Antibodies for Cancer Therapy," Cancer Res. 69(12):4941-4944 (2009). |
Bargou, R., et al., "Tumor Regression in Cancer Patients by Very Low Doses of a T-Cell Engaging Antibody," Science 321:974-977 (2008). |
Becker-Herman S, et al. CD74 is a member of the regulated intramembrane proteolysis-processed protein family. Mol Biol Cell. 16(11):5061-9. Nov. 2005. Epub Aug. 17, 2005. |
Bellosillo, B., et al., "Complement-Mediated Cell Death Induced by Rituximab in B-Cell Lymphoproliferative Disorders is Mediated in vitro by a Caspase-Independent Mechanism Involving the Generation of Reactive Oxygen Species," Blood 98(9):2771-2777 (2001). |
Bertilaccio, M.T.S., et al., "A Novel Rag2-−1−-c−1−-Xenograft Model of Human CLL," Blood 115(8):1605-1609 (2010). |
Bertilaccio, M.T.S., et al., "A Novel Rag2--1--c-1--Xenograft Model of Human CLL," Blood 115(8):1605-1609 (2010). |
Bonnet, D. and Dick, J.E., "Human Acute Myeloid Leukemia is Organized as a Hierarchy that Originates from a Primitive Hematopoietic Cell," Nat. Med. 3(7):730-737 (1997). |
Borche L, et al. CD43 monoclonal antibodies recognize the large sialoglycoprotein of human leukocytes. Eur J Immunol. 17(10)1523-6. Oct. 1987. |
Brodsky FM. A matrix approach to human class II histocompatibility antigens: reactions of four monoclonal antibodies with the products of nine haplotypes. Immunogenetics. 19(3):179-94. 1984. |
Bruhl, H., et al., "Depletion of CCR5-Expressing Cells with Bispecific Antibodies and Chemokine Toxins: A New Strategy in the Treatment of Chronic Inflammatory Diseases and HIV," The Journal of Immunology, vol. 166, pp. 2420-2426 (2001). |
Carter, P.J., "Introduction to Current and Future Protein Therapeutics: A Protein Engineering Perspective," Exp. Cell Res. 317:1261-1269 (2011). |
Carter, P.J., "Potent Antibody Therapeutics by Design," Nat. Rev. Immunol 6:343-357 (2006). |
Chinese Office Action in corresponding CN application No. 201280024084.1, dated Jul. 21, 2015. |
Clark, E.A., et al., "Role of Bp35 Cell Surface Polypeptide in Human B-Cell Activation," Proc. Natl. Acad. Sci. 82:1766-1770 (1985). |
Clarke, et al., "Gemtuzumab Ozogamicin: Is There Room for Salvage?" Blood 116(14):2618-2619 (2010). |
Cochran et al., J. Immunol. Meth. 287: 147-158, 2004. * |
De Groot, A.S., et al., "Activation of Natural Regulatory T Cells by IgG Fe-derived Peptide 'Tregitopes'," Blood 112(8):3303-3311 (2008). |
Deckert M, et al. CD59 molecule: a second ligand for CD2 in T cell adhesion. Eur J Immunol. 22(11):2943-7. Nov. 1992. |
Dermer et al, Bio/Technology 12: 320, 1994. * |
Donda, A., et al., "In vivo Targeting of an Anti-Tumor Antibody Coupled to Antigenic MHC Class I Complexes Induces Specific Growth Inhibition and Regression of Established Syngeneic Tumor Grafts," Cancer Immunity 3:11 (2003). |
Duncan RJS et al., "A new reagent which may be used to introduce sulfhydryl groups into proteins, and its use in the preparation of conjugates for immunoassay," Analytical Biochemistry, 132(1):68-73 (Jul. 1, 1983). |
Duncan, R.J.S., et al., "A New Reagent Which May be Used to Introduce Sulfhydryl Groups into Proteins, and its Use in the Preparation of Conjugates for Immunoassay," Analytical Biochemistry 132:68-73 (1983). |
Eberl et al., Clin Exp Immunol 114: 173-178, 1998. * |
Eberl, G., et al., "An Anti-CD19 Antibody Coupled to a Tetanus Toxin Peptide Induces Efficient Fas Ligand (FasL)-Mediated Cytotoxicity of a Transformed Human B Cell Line by Specific CD4+T Cells," Clinical and Experimental Immunology 114:173-178 (1998). |
Engleman EG, et al. Studies of a human T lymphocyte antigen recognized by a monoclonal antibody. Proc Natl Acad Sci U S A. 78(3):1791-5. Mar. 1981. |
Eno-Amooquaye, E.A., et al., "Altered Biodistribution of an Antibody-Enzyme Conjugae Modified with Polyethylene Glycol," Br. J. Cancer 73:1323-1327 (1996). |
Epstein AL, et al. Two new monoclonal antibodies (LN-1, LN-2) reactive in B5 formalin-fixed, paraffin-embedded tissues with follicular center and mantle zone human B lymphocytes and derived tumors. J Immunol. 133 (2):1028-1036. Aug. 1984. |
European Office Action in corresponding EP Application No. 12718715.1, dated Jul. 23, 2015. |
Fattah, O.M., et al., "Peptabody-EGF: A Novel Apoptosis Inducer Targeting ErbB1 Receptor Overexpressing Cancer Cells," Int. J. Cancer 119:2455-2463 (2006). |
First Office Action and Search Report from the State Intellectual Property Office of the People's Republic of China for Application No. 201280024084.1, issued Nov. 15, 2014 (18 pages). |
Fluhr H, et al. Interferon-gamma and tumor necrosis factor-alpha sensitize primarily resistant human endometrial stromal cells to Fas-mediated apoptosis. J Cell Sci. 120(Pt 23):4126-33. Dec. 1, 2007; Epub Nov. 14, 2007. |
Germain, C., et al., "MHC Class I-Related Chain A Conjugated to Antitumor Antibodies can Sensitize Tumor Cells to Specific Lysis by Natural Killer Cells," Clin. Cancer Res 11(20):7516-7522 (2005). |
Ghanekar et al., Gamma Interferon Expression in CD8+ T Cells is a Marker for Circulating Cytotoxic T Lymphocytes that Recognize an HLA A2-Restricted Epitope of Human Cytomegalovirus Phosphoprotein p65, Clin Diagn Lab Immunol 8(3):628-31 (2001). |
Giovannoni, L., et al., "Isolation of Anti-angiogenesis Antibodies from a Large Combinatorial Repertoire by Colony Filter Screening," Nucleic Acids Research 29(5):E27 (2001). |
Golay et al., Archives of Biochemistry and Biophysics 526: 146-153, 2012. * |
Grimbert P. Thrombospondin/CD47 interaction: a pathway to generate regulatory T cells from human CD4+ CD25-T cells in response to inflammation. J Immunol. 177(6):3534-41. Sep. 15, 2006. |
Gura et al., Science 278: 1041-1042, Nov. 1997. * |
Hellström, I., et al., "Monoclonal Mouse Antibodies Raised Against Human Lung Carcinoma," Cancer Research 46:3917-3923 (1986). |
Hislop, A.D., et al., "Cellular Responses to Viral Infection in Humans: Lessons from Epstein-Barr Virus," Annu. Rev. Immunol. 25:587-617 (2007). |
Horie R, Watanabe T. CD30: expression and function in health and disease. Semin Immunol. 10(6):457-70. Dec. 1998. |
Howland, S.W., et al., "Inducing Efficient Cross-Priming Using Antigen-Coated Yeast Particles," J. Immunother. 31(7):607-619 (2008). |
Hughes, B., "Antibody-Drug Conjugates for Cancer: Poised to Deliver?," Nature Reviews Drug Discovery 9:665-667 (2010). |
International Preliminary Report on Patentability for International Application PCT/GB2012/050577; issued on Sep. 17, 2013. |
International Preliminary Report on Patentability for PCT/GB2013/050499 issued on Sep. 2, 2014. |
International Search Report and Written Opinion of the International Searching Authority for International Application No. PCT/GB2012/050577, "Re-Directed Immunotherapy," Date of Mailing: Jun. 29, 2012. |
International Search Report for PCT/GB2013/050499 mailed on Jul. 24, 2013. |
International Search Report for PCT/GB2013/052427 dated May 2, 2014. |
Irvine, D.J., et al., "Direct Observation of Ligand Recognition by T Cells," Nature 419:845-849 (2002). |
Jeffrey, S.C., et al., "Dipeptide-Based Highly Potent Doxorubicin Antibody Conjugates," Bioorganic & Medicinal Chemistry Letters 16:358-362 (2006). |
Jilaveanu LB, et al. CD70 expression patterns in renal cell carcinoma. Hum Pathol. 43(9):1394-9. Sep. 2012; Epub Mar. 7, 2014. |
Jubala et al., Vet Pathol 42: 468-476, 2005. * |
Jutila MA, et al. L-selectin serves as an E-selectin ligand on cultured human T lymphoblasts. J Immunol. 169 (4):1768-73. Aug. 15, 2002. |
Kawamura, K.S., et al., "In Vivo Generation of Cytotoxic T Cells from Epitopes Displayed on Peptide-Based Delivery Vehicles," Journal of Immunology 168:5709-5715 (2002). |
Klechevsky E, et al. Cross-priming CD8+ T cells by targeting antigens to human dendritic cells through DCIR. Blood. 116(10):1685-97. Sep. 9, 2010; Epub Jun. 7, 2010. |
Kohler, et al., "Continuous Cultures of Fused Cells Secreting Antibody of Predefined Specificity," Nature 256:495-497 (1975). |
Kozak, R.W., et al., "IL-2-PE40 Prevents the Development of Tumors in Mice Injected with IL-2 Receptor Expressing EL4 Transfectant Tumor Cells," Journal of Immunology 145 (8):2766-2771 (1990). |
Kreitman RJ, et al. Phase I trial of anti-CD22 recombinant immunotoxin moxetumomab pasudotox (CAT-8015 or HA22) in patients with hairy cell leukemia. J Clin Oncol. 230(15):1822-8. May 20, 2012; Epub Feb. 21, 2012. |
Kufer, P., et al., "Construction and Biological Activity of a Recombinant Bispecific Single-Chain Antibody Designed for Therapy of Minimal Residual Colorectal Cancer," Cancer Immunology Immunotherapy, vol. 45, pp. 193-197 (1997). |
Lagadec P, et al. Involvement of a CD47-dependent pathway in platelet adhesion on inflamed vascular endothelium under flow. Blood. 101(12):4836-43. Jun. 15, 2003; Epub Feb. 27, 2003. |
Lamb CA, et al. Invariant chain targets HLA class II molecules to acidic endosomes containing internalized influenza virus. Proc Natl Acad Sci U S A. 88(14):5998-6002. Jul. 15, 1991. |
Larche, M., et al., "Functional Evidence for a Monoclonal Antibody that Binds to the Human IL-4 Receptor," Immunology 65:617-622 (1988). |
Lash, A., "Making the Case for Antibody-Drug Conjugates," In Vivo: The Business and Medicine Report:32-38 (2010). |
Lehmann JC, et al. Overlapping and selective roles of endothelial intercellular adhesion molecule-1 (ICAM-1) and ICAM-2 in lymphocyte trafficking. J Immunol. 171(5):2588-93. Sep. 1, 2003. |
Lesley J, Trowbridge IS. Genetic characterization of a polymorphic murine cell-surface glycoprotein. Immunogenetics. 15(3):313-20. Mar. 1982. |
Li, S, et al., "Analysis of FOXP3+ regulatory T cells that display apparent viral antigen specificity during chronic hepatitis C virus infection," PLoS Pathog. Dec. 2009;5(12):e1000707. Epub Dec. 24, 2009. |
Loffler et al. "A recombinant bispecific single-chain antibody, CD19×CD3, induces rapid and high lymphoma-directed cytotoxicity by unstimulated T lymphocytes." 95(6):2098-103. (Mar. 15, 2000). |
Loffler, A., et al., "A Recombinant Bispecific Single-Chain Antibody, CD19×CD3, Induces Rapid and High Lymphoma-Directed Cytotoxicity by Unstimulated T Lymphocytes," Blood Journal, 95(6): 2098-20103 (Mar. 15, 2000). |
Loisel, S., et al., "Establishment of a Novel Human B-CLL-like Xenograft Model in Nude Mouse," Leukemia Research 29:1347-1352 (2005). |
Lorberboum-Galski, H., et al., "Cytotoxic Activity of an Interleukin 2-Pseudomonas Exotoxin Chimeric Protein Produced in Escherichia coli," Proc. Natl. Acad. Sci 85:1922-1926 (1988). |
Lutterbuese R. et al., "T cell-engaging BiTE antibodies specific for EGFR potently eliminate KRAS- and BRAF-mutated colorectal cancer cell", Proc. Natl. Acad. Sci. 107(28):12605-12610. (Jul. 13, 2010). |
Lutterbuese, R., et al., "Potent Control of Tumor Growth by CEA/CD3-bispecific Single-Chain Antibody Constructs that are not Competitively Inhibited by Soluble CEA," J. Immunother. 32(4):341-352 (2009). |
Mack, M., et al., "A Small Bispecific Antibody Construct Expressed as a Functional Single-Chain Molecule With High Tumor Cell Cytotoxicity," Proceedings of the National Academy of Sciences, vol. 93, pp. 7021-7025 (Jul. 1995). |
Mack, M., et al., "Biologic Properties of a Bispecific Single-Chain Anitbody Directed Against 17-1A (EpCAM) and CD3; Tumor Cell-Dependent T Cell Stimulation and Cytotoxic Activity," The Journal of Immunology, vol. 158, pp. 3965-3971 (1997). |
Mahato, R., et al., "Prodrugs for Improving Tumor Targetability and Efficiency," Adv. Drug. Deliv. Rev. 63(8):659-670 (2011). |
Maiti A et al. TNF-alpha induction of CD44-mediated leukocyte adhesion by sulfation. Science. 282(5390):941-3. Oct. 30, 1998. |
Matsumura, Y. and Maeda, H., "A New Concept for Macromolecular Therapeutics in Cancer Chemotherapy: Mechanism of Tumoritropic Accumulation of Proteins and the Antitumor Agent Smancs," Cancer Res. 46:6387-6392 (1986). |
Mayes, S., et al., "New Antibody Drug Treatments for Lymphoma," Expert Opin. Biol. Ther. 11(5):623-640 (2011). |
Mazor R, et al. Identification and elimination of an immunodominant T-cell epitope in recombinant immunotoxins based on Pseudomonas exotoxin A. Proc Natl Acad Sci U S A. 109(51):E3597-603. Dec. 18, 2012. Epub Dec. 3, 2012. |
Melton, R.G., et al., "Covalent Linkage of Carboxypeptidase G2 to Soluble Dextrams-I," Biochemical Pharmacology 36(1):105-112 (1987). |
Meziere, C., et al., "In Vivo T Helper Cell Response to Retro-Inverso Peptidomimetics," J. Immunol. 159:3230-3237 (1997). |
Molhoj et al. "CD19-/CD3-bispecific antibody of the BiTE class is far superior to tandem diabody with respect to redirected tumor cell lysis", Mol Immunol. 44(8):1935-1943. (Dec. 1, 2006). |
Moore, P.A., et al., "Application of Dual Affinity Retargeting Molecules to Achieve Optimal Redirected T-Cell Killing of B-Cell Lymphoma," Blood 117(17):4542-4551 (2011). |
Mous et al., "Redirection of CMV-specific CTL towards B-CLL via CD20-targeted HLA/CMV complexes," Leukemia 20, pp. 1096-1102 (2006). |
Mous et al., Leukemia 20: 1096-1102, 2006. * |
Murphy, G., "The ADAMs: Signalling Scissors in the Tumour Microenvironment," Nature Reviews Cancer 8:929-941 (2008). |
Non-Final Office Action in corresponding U.S. Appl. No. 14/005,452, dated Jul. 31, 2015. |
Ogg, G.S., et al., "Sensitization of Tumour Cells to Lysis by Virus-Specific CTL using Antibody-Targeted MHC Class I/Peptide Complexes," British Journal of Cancer 82(5):1058-1062 (2000). |
Onda M, et al. An immunotoxin with greatly reduced immunogenicity by identification and removal of B cell epitopes. Proc Natl Acad Sci U S A. 2105(32):11311-6. Aug. 12, 2008; Epub Aug. 4, 2008. |
Osborn L, et al. Amino acid residues required for binding of lymphocyte function-associated antigen 3 (CD58) to its counter-receptor CD2. J Exp Med. 181(1):429-34. Jan. 1995. |
O'Sullivan MK, et al., "Comparison of two methods of preparing enzyme-antibody conjugates: application of these conjugates for enzyme immunoassay," Anal Biochem. Nov. 15, 1979;100(1):100-8. |
O'Sullivan, M.J., et al., "Comparison of Two Methods of Preparing Enzyme-Antibody Conjugates: Application of these Conjugates for Enzyme Immunoassay," Analytical Biochemistry 100:100-108 (1979). |
Park, B.-W., et al., "Rationally Designed Anti-HER2/neu Peptide Mimetic Disables P185HER2/neu Tyrosine Kinases in vitro and in vivo," Nature Biotechnology 18:194-198 (2000). |
Plant, A, et al., "Phospholipid/Alkanethiol Bilayers for Cell-Surface Receptor Studies by Surface Plasmon Resonance," Analytical Biochemistry, vol. 226, pp. 342-348 (1995). |
Polski JM and Janney CG. Ber-H2 (CD30) immunohistochemical staining in malignant melanoma. Mod Pathol. 12 (9):903-6. Sep. 1999. |
Ponde, D.E., et al., "Development of Anti-EGF Receptor Peptidomimetics (AERP) as Tumor Imaging Agent," Bioorganic & Medicinal Chemistry Letters 21:2550-2553 (2011). |
Poon, KA, "Safety Assessment of Antibody Drug Conjugates," Presentation at Northern California Society of Toxicology. May 6, 2010. |
Porcelli, S., et al., "Recognition of Cluster of Differentiation 1 Antigens by Human CD4-CD8- Cytolytic T Lymphocytes," Nature341:447-450 (1989). |
Rader, C., "DARTs Take Aim at BiTEs," Blood 117:4403-4404 (2011). |
Rajasagi M. CD44 promotes progenitor homing into the thymus and T cell maturation. J Leukoc Biol. 85(2):251-61. Feb. 2009; Epub Oct. 27, 2008. |
Rawlings, N.D., et al., "MEROPS: the Peptidase Database," Nucleic Acids Research 36:D320-D325 (2008). |
Response to Office Action from European Patent Office dated Nov. 8, 2013, filed Apr. 14, 2014, for European Patent Application No. 12718715.1 (21 pages). |
Rich, D.H., "Inhibitors of cysteine proteases." In Research monographs in cell and tissue physiology vol. 12, Proteinase inhibitors. Barrett AJ, Salvesen G, eds. (Amsterdam: Elsevier.) pp. 153-178 (1986). |
Romagnoli, P., et al., "Selective Interaction of Ni with an MHC-Bound Peptide," The EMBO Journal 10(6):1303-1306 (1991). |
Romero, P., et al., "Photoaffinity Labeling of the T Cell Receptor on Living Cytotoxic T Lymphocytes," The Journal of Immunology 150(9):3825-3831 (1993). |
Sathish et al., Nature Reviews Drug Discovery 12: 306-324, Apr. 2013. * |
Savage, P., et al. "Induction of Viral and Tumour Specific CTL Responses Using Antibody Targeted HLA Class I Peptide Complexes," British Journal of Cancer 86:1336-1342 (2002). |
Savage, P., et al., "Induction of Viral and Tumour Specific CTL Responses Using Antibody Targeted HLA Class I Peptide Complexes," British Journal of Cancer 86:1336-1342 (2002). |
Schaffitzel, C., et al., "Ribosome Display: an in vitro Method for Selection and Evolution of Antibodies from Libraries," Journal of Immunological Methods 231:119-135 (1999). |
Schmiegel, W., et al., "Cytokine-Mediated Enhancement of Epidermal Growth Factor Receptor Expression Provides an Immunological Approach to the Therapy of Pancreatic Cancer," Proc. Natl. Acad. Sci. 94:12622-12626 (1997). |
Search report from Intellectual Property Office for GB1216649 dated Jan. 17, 2013. |
Searle, F., et al., "A Human Choriocarcinoma Xenograft in Nude Mice; a Model for the Study of Antibody Localization," British Journal Cancer 44:137-144 (1981). |
Senter, P.D., et al., "Anti-Tumor Effects of Antibody-Alkaline Phosphatase Conjugates in Combination with Etoposide Phosphate," Proc. Natl. Acad. Sci. 85:4842-4846 (1988). |
Shen, L., et al., "Important Role of Cathepin S in Generating Peptides for TAP-Independent MHC Class I Crosspresentation in Vivo," Immunity 21:155-165 (2004). |
Sherman, D.B. and Spatola, A.F., "Compatibility of Thioamides with Reverse Turn Features: Synthesis and Conformational Analysis of Two Model Cyclic Pseudopeptides Containing Thioamides as Backbone Modifications," J. Am. Chem. Soc. 112:433-441 (1990). |
Small, E.J., et al., "Placebo-Controlled Phase III Trial of Immunologic Therapy with Sipuleucel-T (APC8015) in Patients with Metastatic, Asymptomatic Hormone Refractory Prostate Cancer," Journal of Clinical Oncology 24(19):3089-3094 (2006). |
Smith, D.C., et al., "Exogenous Peptides Delivered by Ricin Require Processing by Signal Peptidase for Transporter Associated with Antigen Processing-Independent MHC Class I-Restricted Presentation," J. Immunol. 169:99-107 (2002). |
Staerz, U., et al., "Hybrid Antibodies Can Target Sites for Attack by T Cells," Nature, vol. 314, pp. 628-631 (Apr. 1985). |
Staerz, U.D. and Bevan, M.J., "Hybrid Hybridoma Producing a Bispecific Monoclonal Antibody that can Focus Effector T-Cell Activity," Proc. Natl. Acad. Sci 83:1453-1457 (1986). |
Stein R, et al. Epitope specificity of the anti-(B cell lymphoma) monoclonal antibody, LL2. Cancer Immunol Immunother. 37(5):293-8. Oct. 1993. |
Stirnemann, K., et al., "Sustained Activation and Tumor Targeting of NKT Cells Using a CD1d-anti-HER2-scFv Fusion Protein Induce Antitumor Effects in Mice," The Journal of Clinical Investigation, 118(3):994-1005 (2008). |
Sumida, T, et al., "Regulatory T cell epitope recognized by T cells from labial salivary glands of patients with Sjögren's syndrome," Arthritis Rheum. Dec. 1997;40(12):2271-3. |
Sykulev, Y., et al., "Evidence that a Single Peptide-MHC Complex on a Target Cell can Elicit a Cytolytic T Cell Response," Immunity 4:565-571 (1996). |
Sylwester, A.W., et al., "Broadly Targeted Human Cytomegalovirus-Specific CD4+ and CD8+ T Cells Dominate the Memory Compartments of Exposed Subjects," The Journal of Experimental Medicine 202(5):673-685 (2005). |
Tamiolakis D et al. Distribution of somatostatin in pancreatic ductal adenocarcinoma remodels the normal pattern of the protein during foetal pancreatic development: an immunohistochemical analysis. Clin Exp Med. 5(3):106-11. 2005. |
Thibodeau et al., Oncoimmunology 1(6): 908-916, Sep. 2012. * |
Thorsett, E.D., et al., "Dipeptide Mimics. Conformationally Restricted Inhibitors of Angiotensin-Converting Enzyme," Biochemical and Biophysical Research Communications 111(1):166-171 (1983). |
Tosolini, M., et al., "Clinical Impact of Different Classes of Infiltrating T Cytotoxic and Helper Cells (Thl, Th2, Treg, Th17) in Patients with Colorectal Cancer," Cancer Res. 71(4):1263-1271 (2011). |
Trowbridge IS, et al. Biochemical characterization and cellular distribution of a polymorphic, murine cell-surface glycoprotein expressed on lymphoid tissues. Immunogenetics. 15(3):299-312. Mar. 1982. |
Veber, D.F., et al., "Conformationally Restricted Bicyclic Analogs of Somatostatin," Proc. Natl. Acad. Sci. 75(6):2636-2640 (1978). |
Vita, R., et al., "The Immune Epitope Database 2.0," Nucleic Acids Research 38:D854-D862 (2010). |
Waldman, T.A., et al., "Immune Receptors: Targets for Therapy of Leukemia/Lymphoma, Autoimmune Diseases and for the Prevention of Allograft Rejection," Annu. Rev. Immunol. 10:675-704 (1992). |
Wang, Q.-C., et al., "Induction of Hepatitis C Virus-Specific Cytotoxic T and B Cell Responses by Dendritic Cells Expressing a Modified Antigen Targeting Receptor," World Journal of Gastroenterology 11(4):557-560 (2005). |
Wang, Q-C., et al., "Induction of Hepatitis C Virus-Specific Cytotoxic T and B Cell Responses by Dendritic Cells Expressing a Modified Antigen Targeting Receptor," World Journal of Gastroenterology, vol. 11, No. 4, Jan. 28, 2005, pp. 557-560. |
Webb, S, et al., "Pharma interest surges in antibody drug conjugates," Nat Biotechnol. Apr. 2011;29(4):297-8. |
Winter, G., et al., "Making Antibodies by Phage Display Technology," Annu. Rev. Immunol. 12:433-455 (1994). |
Witte et al., Cancer and Metastasis Reviews 17: 155-161, 1998. * |
Written Opinion of the International Searching Authority for PCT/GB2013/050499 dated Jul. 24, 2013. |
Wu et al., Nature Biotechnology 23(9): 1137-1146, Sep. 2005. * |
Yu et al., Investigative Ophthalmology & Visual Science 49(2): 522-527, Feb. 2008. * |
Zhou, X., et al., "The Role of Complement in the Mechanism of Action of Rituximab for B-Cell Lymphoma: Implications for Therapy," The Oncologist 13:954-966 (2008). |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20160106862A1 (en) * | 2011-03-17 | 2016-04-21 | The University Of Birmingham | Re-Directed Immunotherapy |
US10287321B2 (en) * | 2011-03-17 | 2019-05-14 | The University Of Birmingham | Re-directed immunotherapy |
US11236131B2 (en) | 2011-03-17 | 2022-02-01 | The University Of Birmingham | Re-directed immunotherapy |
US11759444B2 (en) | 2015-07-31 | 2023-09-19 | The Johns Hopkins University | Methods for cancer and immunotherapy using prodrugs of glutamine analogs |
WO2020162696A1 (ko) * | 2019-02-08 | 2020-08-13 | 주식회사 굳티셀 | 암 치료를 위한 t 세포의 활성화 방법 |
Also Published As
Publication number | Publication date |
---|---|
EP3138581B1 (en) | 2019-01-02 |
US20190270779A1 (en) | 2019-09-05 |
AU2016259343B2 (en) | 2018-06-28 |
US20150250868A1 (en) | 2015-09-10 |
CN103561771A (zh) | 2014-02-05 |
US20140004081A1 (en) | 2014-01-02 |
JP6449933B2 (ja) | 2019-01-09 |
CN103561771B (zh) | 2019-01-04 |
CA2830349C (en) | 2019-07-16 |
AU2012228100B2 (en) | 2016-09-08 |
US11236131B2 (en) | 2022-02-01 |
JP6130307B2 (ja) | 2017-05-17 |
JP2014509605A (ja) | 2014-04-21 |
EP2686020B1 (en) | 2017-02-22 |
WO2012123755A1 (en) | 2012-09-20 |
JP2017171665A (ja) | 2017-09-28 |
US10287321B2 (en) | 2019-05-14 |
CN110038135A (zh) | 2019-07-23 |
EP3138581A1 (en) | 2017-03-08 |
DK2686020T3 (en) | 2017-05-01 |
US9358282B2 (en) | 2016-06-07 |
AU2016259343A1 (en) | 2016-12-01 |
US20160106862A1 (en) | 2016-04-21 |
DK3138581T3 (en) | 2019-04-15 |
EP2686020A1 (en) | 2014-01-22 |
CN110038135B (zh) | 2021-03-05 |
CA2830349A1 (en) | 2012-09-20 |
AU2012228100A1 (en) | 2013-10-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11236131B2 (en) | Re-directed immunotherapy | |
US10106621B2 (en) | Immunotherapeutic molecules and uses | |
EP3246334B1 (en) | Immunotherapy |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: THE UNIVERSITY OF BIRMINGHAM, UNITED KINGDOM Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:COBBOLD, MARK;MILLAR, DAVID;REEL/FRAME:032324/0587 Effective date: 20120530 |
|
ZAAA | Notice of allowance and fees due |
Free format text: ORIGINAL CODE: NOA |
|
ZAAB | Notice of allowance mailed |
Free format text: ORIGINAL CODE: MN/=. |
|
STCF | Information on status: patent grant |
Free format text: PATENTED CASE |
|
MAFP | Maintenance fee payment |
Free format text: PAYMENT OF MAINTENANCE FEE, 4TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1551); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY Year of fee payment: 4 |
|
FEPP | Fee payment procedure |
Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
LAPS | Lapse for failure to pay maintenance fees |
Free format text: PATENT EXPIRED FOR FAILURE TO PAY MAINTENANCE FEES (ORIGINAL EVENT CODE: EXP.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
STCH | Information on status: patent discontinuation |
Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |